Born the fourth son of William I, Count of Burgundy, one of the wealthiest rulers in Europe, Guy was a member of the highest aristocracy in Europe. His family was part of a network of noble alliances. He was a cousin of Arduin of Ivrea, the King of Italy. One sister, Gisela, was married to Humbert II, Count of Savoy, and then to Renier I of Montferrat; another sister, Maud, was the wife of Odo I, Duke of Burgundy. His brother Raymond was married to Urraca, the heiress of León, and fathered the future King Alfonso VII of León. His brother Hugh was an Archbishop of Besançon.
Guy first appears in contemporary records when he became the Archbishop of Vienne in 1088. He held strong pro-Papal views about the Investiture Controversy. As archbishop, he was appointed papal legate to France by Pope Paschal II during the time that Paschal was induced under pressure from Holy Roman Emperor Henry V to issue the Privilegium of 1111, by which he yielded much of the papal prerogatives that had been so forcefully claimed by Pope Gregory VII in the Gregorian Reforms. These concessions were received with violent opposition and nowhere more so than in France, where the opposition was led by Guy, who was present at the Lateran Synod of 1112.
On his return to France, he immediately convened an assembly of French and Burgundian bishops at Vienne, where the imperial claim to a traditional lay investiture of the clergy was denounced as heretical and a sentence of excommunication was now pronounced against Henry V on the grounds that he had extorted the Privilegium from Paschal II by means of violence. These decrees were sent to Paschal II with a request for a confirmation, which they received on 20 October 1112.
Guy was later, apparently, created cardinal by Pope Paschal, though the latter does not seem to have been quite pleased with his zeal in his attacks upon Henry V. During the violent confrontations between Henry V and Paschal II's successor, Pope Gelasius II, the Pope was forced to flee from Rome, first to Gaeta, where he was crowned, then to the Abbey of Cluny, where he died on 29 January 1119.
Archbishop Guy de Bourgogne of Vienne, France, who was not a cardinal, was elected at Cluny on 2 February 1119. Nine cardinals took part in the election. Most of the other cardinals were in Rome. He was crowned at Vienne on 9 February 1119, as Calixtus II.
At the outset, it appeared that the new Pope was willing to negotiate with Henry V, who received the papal embassy at Strasbourg, and withdrew his support from the antipope he had proclaimed at Rome. It was agreed that pope and emperor should meet at the Château de Mousson, near Rheims, and in October the new Pope opened the council at Rheims attended by Louis VI of France with most of the barons of France and more than four hundred bishops and abbots. Henry V arrived for his personal conference at Mousson — not alone, as had been anticipated, but with an army of over thirty thousand men. Calixtus II, fearing that force was likely to be used to extract prejudicial concessions, remained at Rheims. There, Calixtus II busied himself ineffectively with attempting a reconciliation between the brothers Henry I of England and Robert II, Duke of Normandy, and the council dealt with disciplinary regulations and decrees against lay investiture, simony, and clerical concubines. Since there was no compromise coming from Henry V, it was determined on 30 October 1119 that the Emperor and his antipope should be solemnly excommunicated.
Returning to Italy, where antipope Gregory VIII was supported in Rome by imperial forces and Italian allies of the emperor, Calixtus II managed to gain the upper hand amid clear demonstrations of popular support. The Imperial candidate was obliged to flee to the fortress of Sutri, where he was taken prisoner through the intervention of Norman support from the Kingdom of Naples. He was transferred from prison to prison first near Salerno, and afterwards at the fortress of Fumo. The imperial allies in Rome soon disbanded.
In 1120 Calixtus II issued the papal bull Sicut Judaeis (Latin: "As the Jews") setting out the official position of the papacy regarding the treatment of Jews. It was prompted by the First Crusade, during which over five thousand Jews were slaughtered in Europe. The bull was intended to protect Jews and echoed the position of Pope Gregory I that Jews were entitled to "enjoy their lawful liberty." The bull forbade Christians, on pain of excommunication, from forcing Jews to convert, from harming them, from taking their property, from disturbing the celebration of their festivals, and from interfering with their cemeteries.
It was reaffirmed by popes Alexander III, Celestine III (1191-1198), Innocent III (1199), Honorius III (1216), Gregory IX (1235), Innocent IV (1246), Alexander IV (1255), Urban IV (1262), Gregory X (1272 & 1274), Nicholas III, Martin IV (1281), Honorius IV (1285-1287), Nicholas IV (1288–92), Clement VI (1348), Urban V (1365), Boniface IX (1389), Martin V (1422), and Nicholas V (1447).
Having established his power in Italy, the Pope resolved to re-open negotiations with Henry V on the question of investiture. Henry V was anxious to put an end to a controversy which had reduced imperial authority in Germany — terminally so, as it appeared in the long run. An embassy of three cardinals was sent by Calixtus II to Germany, and negotiations for a permanent settlement of the investiture struggle were begun in October 1121 at Würzburg, where it was agreed that a general truce should be proclaimed in Germany, that the Church should have free use of its possessions, and that the lands of those in rebellion should be restored. These decrees were communicated to Calixtus II, who despatched the legate Lambert to assist at the synod that had been convoked at Worms, where, on 23 September 1122, the agreement known as the Concordat of Worms was concluded. On his side the Emperor abandoned his claim to investiture with ring and crosier, and granted freedom of election to episcopal sees. On the papal side, it was conceded that the bishops should receive investiture with the sceptre, that the episcopal elections should be held in the presence of the Emperor or his representatives, that in case of disputed elections the Emperor should, after the decision of the metropolitan and the suffragan bishops, confirm the rightfully elected candidate, and lastly, that the imperial investiture of the temporal properties connected to the sees should take place in Germany before the consecration. In Burgundy and in Italy the imperial investiture would take place after the consecration ceremony, while in the Papal States the pope alone had the right of investiture, without any interference on the part of the Emperor. As a result of this Concordat, the Emperor still retained in his hands the controlling influence in the election of the bishops in Germany, though he had abandoned much in regard to episcopal elections in Italy and Burgundy.
To secure the confirmation of this Concordat of Worms, Calixtus II convened the First Lateran Council on 18 March 1123. It solemnly confirmed the Concordat and passed several disciplinary decrees, such as those against simony and concubinage among the clergy. Decrees were also passed against violators of the Truce of God, church-robbers, and forgers of ecclesiastical documents. The indulgences already granted to the crusaders were renewed, and the jurisdiction of the bishops over the clergy, both secular and regular, was more clearly defined.
Calixtus II devoted his last few years to re-establishing papal control over the Campagna and establishing the primacy of his See of Vienne over the See of Arles, an ancient conflict. He rebuilt the church of Santa Maria in Cosmedin in Rome.
Calixtus II died 13 December 1124.