With the backing of the European media tycoon Sir Lew Grade (the head of the British broadcast network ATV) and the Italian film producer Carlo Ponti, the international all-star cast was expected to attract a widespread audience, with rights sold prior to filming, to both British and American distributors. Ponti also saw the production as a showcase for his wife, Sophia Loren.
When the existence of a strain of plague (vaguely identified as pneumonic) is revealed at the US mission at the International Health Organization, three terrorists seek to blow up the US mission. Two of them are shot, one mortally, by security personnel but one escapes. The surviving terrorist is hospitalised and quarantined and identified as Swedish. Dr. Elena Stradner (Ingrid Thulin) and US Colonel Stephen Mackenzie (Burt Lancaster) (Military Intelligence assigned to the IHO) argue over the nature of the strain, which Stradner suspects is a biological weapon but which Colonel Mackenzie claims was in the process of being destroyed.
The third terrorist (Lou Castel) escapes and stows away on a train bound from Geneva to Stockholm. Dr. Stradner believes that the train should be stopped so that the terrorist can be removed and quarantined, but Col. Mackenzie is concerned that all of the passengers on the train might be infected. Mackenzie insists on rerouting the train to an abandoned ex-Nazi railway line to a quarantine camp in Janov, Poland. However, the line crosses a dangerously unsound steel arch bridge known as the Kasundruv Bridge or the "Cassandra Crossing", out of use since 1960 (former railway Zagorz-Solina -Turka – Lviv between Poland and Ukraine)
Mackenzie understands that the bridge might collapse as the train passes over it. The presence of the infected terrorist, and the rerouting of the train, precipitates the second conflict, among passengers on the train; they include Dr. Jonathan Chamberlain (Richard Harris), a famous neurologist, his ex-wife Jennifer Rispoli Chamberlain (Sophia Loren), and Nicole Dressler (Ava Gardner), the wife of a German arms dealer. She is embroiled in an affair with her young companion Robby Navarro (Martin Sheen). Navarro is a heroin trafficker being pursued by FBI agent Haley (O. J. Simpson), who is travelling undercover as a priest.
Mackenzie informs Dr. Chamberlain of the presence of the terrorist, who is found, but attempts to remove him via a helicopter are unsuccessful because the train enters a tunnel. Chamberlain is also told that the plague has a 60% mortality rate. Mackenzie, however, informs passengers that police have received reports of anarchist bombs placed along the rail line, and that the train will be rerouted to Nuremberg. There the train is sealed with an enclosed oxygen system and a US Army medical team is placed aboard, with the now-deceased terrorist being placed in a hermetically-sealed coffin. Dr. Chamberlain learns of the risk of the Cassandra Crossing. He also begins to suspect the disease is not as serious as originally thought: few of the passengers have become infected and few of those have actually died. He radios MacKenzie suggesting the infected portion of the train be uncoupled and isolated, but MacKenzie has no intention of stopping the train: if, as expected, the Cassandra Crossing collapses, it will neatly cover the fact that the U.S has been harbouring germ warfare agents in a neutral country. Passengers on the train work together to stop the train before it reaches the Cassandra Crossing.
The passengers manage to seize the back half of the train roughly one km before the bridge and detach it, hoping that with less weight, the front half will cross safely. But the bridge collapses, killing everyone aboard the front half. The back end applies the brakes and stops just before reaching the downed bridge. In Geneva, both Stradner and MacKenzie depart: she keeps hope of survivors while he thinks the elimination of the train means no investigations. A guard on duty orders both of them be watched.
As appearing in The Cassandra Crossing, (main roles and screen credits identified):
The Cinecittà studios in Rome were chosen for interiors, with French and Swiss locales providing most of the location footage. The steel arch bridge depicted in the film is actually the Garabit Viaduct in southern France, built from 1880 to 1884 by Gustave Eiffel, who later constructed the Eiffel tower.
At the beginning of the film, passengers arrive at Geneva railway station to embark on the train. The scenes were shot at Basel central station. Where Dr. Chamberlain enters the station, the green coloured trams (belonging to the Basel public transport company BVB), and Basel's Central Station Square can be seen in the background. Many scenes were shot on the railway line Basel – Delémont – Porrentruy; the railway viaduct at St. Ursanne can be recognised most easily.
Much of the film's special effects involved models and rear screen work that was largely effective, although the studio artwork shows a typical US diesel locomotive that doesn't resemble anything seen in the film.
Peter O'Toole was offered the lead role, but he turned it down. Richard Harris played the part instead.
The Cassandra Crossing was only the second film made by Lee Strasberg. Ava Gardner said "the real reason I'm in this picture is money, baby, pure and simple." Tom Mankiewicz, who worked on the script, dubbed the film "The Towering Germ".
The Cassandra Crossing did not fare well with critics or American audiences as disaster films were no longer a guaranteed box office success. Planned as a star vehicle for Sophia Loren, the large international cast involved illogical casting decisions that were noted by Richard Eder, The New York Times reviewer.
Most contemporary reviews also singled out the implausible plotline although praising the cinematography and Jerry Goldsmith's musical score as noteworthy elements. Variety dismissed the film as, "... a tired, hokey and sometimes unintentionally funny disaster film in which a trainload of disease-exposed passengers lurch to their fate."
The film was booed and hissed at preview screenings by critics.
The graphic scenes of the passengers being killed at the end of the film had ensured an "R" rating in theatres and led to two "censored" and "uncensored" versions being released for broadcast and home media.
The Cassandra Crossing, however, still made money. The producers claimed that they recouped the production costs of the film out of Japan alone.