Negrini began his studies at a very early age as a pianist and conductor under teachers such as Berlin Philharmonic conductor Fritz Zweig, soon conducting his first performance at the age of 13, a two-piano performance of Madama Butterfly with a small local Los Angeles opera company. In his subsequent teen years, he continued conducting local productions of Don Pasquale, Faust, and Lucia di Lammermoor. Negrini made his singing debut at age 15, as Dr. Malatesta in a production of Don Pasquale mounted by a small company known as L'Opera Comique, a group begun by his father, the bass Luciano Negrini, and his mother, the mezzo-soprano Clare Mary Young. In 1978, he graduated from Daniel Murphy High School. At the age of 17, he made his tenor debut as Paolino in USC Opera's production of Il matrimonio segreto. While at USC Opera Workshop, he also did work as a repertoire coach, rehearsing the likes of later Metropolitan Opera singers Suzanna Guzman mezzo-soprano and Thomas Hampson baritone .
Soon afterward, at age 19, he became a finalist in the 1980 Lyric Opera of Chicago auditions, alongside his own student, bass-baritone Rush Tully. There, he was later mentored by Walter Baracchi, the noted repetiteur who had been with Lyric Opera of Chicago for a decade, and Milan's La Scala, who had been there since the late 1950s. This launched a professional singing career for Negrini. Among his most successful performances are his portrayal of the "rock star" Nanki-Poo in Peter Sellars's updated production of The Mikado and his rendition of Don Ramiro in the Gian-Carlo Menotti production of La Cenerentola at the Kennedy Center in Washington, D.C. - a role he would eventually perform over 100 times. During this period he also performed the role of David in Die Meistersinger with the Chicago Symphony Orchestra under Erich Leinsdorf.
He made history at Lyric Opera of Chicago, when in 1982 at the age of 21, he replaced Gösta Winbergh as Ferrando in Così fan tutte, making him the youngest tenor ever to sing a leading role there.
In the late 1980s, while continuing to sing throughout the United States, in such roles as Hoffman in The Tales of Hoffman, Lord Percy in Anna Bolena and Dick Johnson in La fanciulla del West, he was approached by Hal Prince to re-create the role of Ubaldo Piangi in Andrew Lloyd Webber's The Phantom of the Opera, for its Los Angeles premiere. This would take Negrini through 8 years and over 3,000 performances of that role, in both Los Angeles and San Francisco.
In the early 1990s he began conducting again, founding the Opera Orchestra of Los Angeles, with business partner Donald Rivers. With that organization, he conducted Verdi's Attila, Puccini's Turandot with Met stars Ghena Dimitrova and Giuliano Ciannella, and An Evening with Jerry Hadley, a gala concert featuring Metropolitan Opera tenor Jerry Hadley. He has also conducted local Los Angeles productions of Tosca, La bohème, Madama Butterfly, and Carmen.
While continuing to sing in such performances as A Gala Vienna New Year's Eve with the San Francisco Symphony under conductor Yves Abel and alongside soprano Lisa Vroman, and the role of Martin in Aaron Copland's The Tender Land for the Cabrillo Music Festival, he also began producing recordings. Some of the best known of these are Broadway Classic which he also conducted, starring Lisa Vroman, and Dangerous Type, starring jazz singer and actress Bettina Devin. In the past two decades, he has maintained teaching studios in both Los Angeles and San Francisco, working with such widely varying talents as Metropolitan Opera tenor Raul Hernandez, Bettina Devin of the film Rent, tenor Franc D'Ambrosio of The Godfather Part III fame, TV and stage star Nancy Dussault, Broadway singing actresses Lisa Vroman, Aneka Noni Rose and Karen Morrow, and the Tony Award-winning Dame Edna.
In the Fall of 2009, he guest starred on the HBO TV series Curb Your Enthusiasm, as an amiable opera-singing restaurant owner who was rudely interrupted by Larry David. In March 2010 he played Tony in Frank Loesser's The Most Happy Fella to great acclaim with the Silicon Valley Symphony (formerly San Jose Symphony). His longtime friend and colleague Lisa Vroman was his Rosabella. In 2011 he performed the role of William Randolph Hearst in the musical W.R. & Daisy, which he also recorded excerpts of. The same year he filmed the leading role of Mr. Benedict in the Indie thriller No One Will Know
In October 2012 he made a guest appearance as Louie on the Fox TV series Bones.
For 2010-2015 he was the resident conductor of the Opera Arts Festival in Palm Desert, California.