After a 30-year career that engendered dozens of bestselling novels of international intrigue, Ludlum died in the spring of 2001, just before publication of The Cassandra Compact, the second title in the Covert-One biotech series, and co-written with Philip Shelby.
After a long absence from the United States Army Military Research Institute for Infectious Diseases (USAMRIID, a real military organization), Jon Smith continues to wander without meaning in his life, upset by the death of his fiancée, Sophia Russell. After meeting Sophia's old childhood friend, Megan Olson, an astronaut and scientist, he has begun to rethink his destiny.
The head of Covert-One, a relatively innocuous man by the name of Nathaniel "Fred" Klein, approaches Jon for his first assignment: the extraction of a Russian military scientist named Yuri Danko, whom, by coincidence, is also a good friend of Jon. Although Jon reaches Yuri and exchanges words with him, Danko is murdered by a pair of Sicilian assassins. Peter Howell – a former SAS officer and MI6 operative – acts as backup support for Jon, and quickly recovers a document off of Danko's body. Upon analysis, they realize that Danko tried to warn them about the planned theft of a smallpox sample from Russia's Bioaparat biological disease research center.
Jon travels to Moscow, where he meets Randi Russell, the sister of his dead fiancée and a CIA agent currently under the guise of a Moscow venture capitalist looking to recruit gifted young Russian trainees as computer analysts for the Central Intelligence Agency. She gives him the name of General Kirov as a trustworthy government liaison. After meeting Smith and being warned about the situation, he and his lieutenant/lover Lara Telegin warn the Russian president about the impending theft. Immediate orders are given to secure Bioaparat.
A Russian guard, however, steals the smallpox sample and gives to Ivan Beria, a Serbian terrorist who is being paid to take the smallpox out of the country. Beria treacherously murders the guard and immediately passes off the sample to Dr. Adam Treloar, a NASA scientist traveling to Russia under the pretense of visiting his dead mother.
At this point, Telegin has been exposed as the traitor within Russia's military, who warned the guard about the cordon to be set at Bioaparat. Kirov, devastated, agrees to help Smith out under all circumstances. They capture an image of Beria and Treloar on tape. Through computer enhancements done by Randi's protégé, Sasha, Treloar is exposed and comes within seconds of being captured by Smith.
Treloar has been secretly working for Dylan Reed, another NASA scientist and colleague of Megan Olson. Reed in turn has been working for Dr. Karl Bauer, the CEO of Bauer-Zermatt A.G., a pharmaceutical company known for its philanthropy – and its secrets during Nazi Germany in World War II. Bauer's allies in the U.S. Government, General Frank Richardson and Deputy Director of the NSA, Anthony Price are the main players in the scheme of the convoluted Cassandra Compact, which revolves around modifying the smallpox into a doomsday virus to use against the enemies of the United States.
Beria is ordered to kill Treloar, who is considered the weak link and a possible liability. After Smith recognizes a connection to NASA, Reed panics and orders Beria to kill Smith. Kirov and Smith, however, anticipating Beria's actions, disable Beria and interrogate him.
Meanwhile, Peter Howell discovers – after a failed attempt on his life – that the U.S. Military is connected to this entire scheme. He also uncovers the name of a Swiss financier who handles the money used by Karl Bauer, and with the help of Smith, he helps uncover the identity of Bauer as the leader of the entire scheme.
Randi, meanwhile, with the help of her protégé Sasha, unlocks the files of the Cassandra Compact found upon Telegin's laptop, and pinpoints Richardson and Price as the moles in the United States government working for Bauer. Smith decoys both men into revealing their secrets to the President, and the moles are killed by a trap made by a team of Klein.
Reed smuggles the smallpox on board the Space Shuttle Discovery, which is bedecked as a laboratory to monitor bacteriological phenomena in space. After the launch, Reed exploits the gravity-free environment of the shuttle to secretly modify the smallpox to become larger and much more potent, gaining the ability to kill within minutes instead of weeks. He releases the smallpox on board, killing most of the crew except for Megan Olson, who is revealed to be a Covert-One agent as well.
After shuttle lands back on Earth, Jon rescues Megan. Bauer, who kills Reed to keep the secret of the smallpox safe, takes the sample but is locked inside the spacecraft by Jon Smith. The auto-destruct sequence destroys the spacecraft, along with the doomsday strain and Karl Bauer, ending the Cassandra Compact. Megan, counted among the dead upon shuttle Discovery, is given a new identity and is reshaped by plastic surgery. The novel ends with Jon Smith laying flowers on Yuri Danko's grave – without whom the world would now be at the mercy of a madman.