Giancana’s various ties to JFK have long been the subject of speculation. The mobster helped raise money for JFK’s crucial West Virginia primary campaign, did JFK send $250,000 with Judy Campbell to him for the mob to get out the union vote and make corrupt unions contribute to JFK's campaign or had he arranged to pay off appropriate political figures? Many historians believe that ballot stuffing in Chicago helped ensure Kennedy’s election in 1960. It has been said that Giancana had agreed to a deal with Joseph Kennedy to guarantee that he would arrange to rig the presidential election in Illinois, to ensure that his son John would become president. Paul “Skinny” D'Amato, a mutual friend of Sinatra's and Giancana's, had used his influence with sheriffs who gambled illegally in Greenbriar County to encourage the coal miners' unions, and anyone else with whom they had influence in the West Virginia area, to vote for the Kennedy ticket.

The Mob had agreed to help the Kennedys, but obviously expected something in return. They did not count on the new president and his brother returning the favour by going after them with a vengeance, by investigating the men that had helped JFK become president in his attempt to stamp out organized crime in America. Giancana had believed Joe when he told him that if he helped John win the election that he would look after the mob.

The relationship between Giancana and the Kennedys was more than business orientated, as they both shared a taste for women – the same women, namely Judy Campbell. Judith admitted to Larry King on television in 1992 that she repeatedly acted as a courier, shipping satchels of money between the Chicago boss and John Kennedy, used to help Kennedy, the underdog, defeat Hubert Humphrey who was the favourite in the election, adding further proof to voter fraud.

In late 1960, was when the friendship turned to hatred between Giancana and the Kennedys. John F. Kennedy appointed his brother Robert as attorney general. Sam Giancana later said that as far as he was concerned, this was a sucker punch he had not expected. Sam had certain favours he had planned to ask of the Kennedys in the near future, and he expected his wishes to be granted because of his involvement in the successful West Virginia primary. However, with Robert as attorney general, he knew that wasn’t going to happen, given RFK’s stance on organized crime.

In March 1961, Giancana told Sinatra he wanted Robert Kennedy to back off from his investigation of his friends, and he wanted Sinatra to talk to Joseph Kennedy about the matter. According to a wiretapped phone conversation between Giancana and Johnny Roselli, Frank had said to Sam, while they were in Florida, "Don't worry about it. If I can't talk to the old man (Joseph Kennedy), I'm gonna talk to the man (Jack Kennedy)." Sinatra convinced Peter Lawford to talk to Bobby Kennedy about Giancana and was told to mind his own business.

Whatever Giancana’s specific link to JFK was, the two men had a nemesis in common: Fidel Castro, whom Mob leaders hated because he had taken over Cuba, with its extensive gambling rackets. The Kennedy Administration, obviously, viewed Castro’s Communist regime as a threat to national security, as evidenced by the infamous Bay of Pigs invasion in April 1961. The tie between Giancana and Kennedy would again be the subject of speculation when information later surfaced that the Mafia and the Central Intelligence Agency (CIA) had joined forces sometime in the 1960s to plot Castro’s assassination. It is believed that Judy was again messenger between JFK and Giancana as they plotted to assassinate Castro.

Towards the end of JFK’s life, Giancana was feeling used and neglected by the Kennedys, who had agreed to look after himself and his outfit. He wanted revenge, he wanted to show them that it was a bad idea to use the Mafia and not expect to have favours asked for in return. Giancana could be a ruthless man, but was he ruthless enough to assassinate JFK?