Hoffa had always cooperated with the Mafia, which helped him with strong-arm and was partners with him in investing Teamsters Union dues and pension funds in legal and illegal enterprises (including Vegas hotels--as in "Casino"). When Hoffa went to prison, Frank Fitzsimmons got cozy with President Nixon and threw his support to Nixon. In return, Nixon offered Hoffa a pardon, but with the proviso that he could not hold a union position until years after he got out of prison. Meanwhile the Mafia found Fitzsimmons easier to deal with than Hoffa.
Hoffa then began making loud noises about how he had lots of incriminating evidence on various Mafia people and would turn government informant unless they accepted his return to power. That's the generally accepted reason for his disappearance. Another (perhaps in parallel): He went to prison with Anthony (Tony Pro) Provenzano, a Mafia bigshot and Teamsters ally. Hoffa continued to get a huge Teamsters salary when he was in prison, but Provenzano got none. He and Provenzano argued violently in prison over this. Some people connect Provenzano's beef with Hoffa's disappearance.
For more on this, read "I Hear You Paint Houses" by Frank (The Irishman) Sheeran, a longtime ally of Hoffa's, who claimed he whacked Hoffa.