On January 14, 2009, Jobs wrote in an internal Apple memo that in the previous week he had "learned that my health-related issues are more complex than I originally thought". He announced a six-month leave of absence until the end of June 2009, to allow him to better focus on his health. Tim Cook, who previously acted as CEO in Jobs's 2004 absence, became acting CEO of Apple, with Jobs still involved with "major strategic decisions".

In 2009, Tim Cook offered a portion of his liver to Jobs, since both share a rare blood type and the donor liver can regenerate tissue after such an operation. Jobs yelled, "I'll never let you do that. I'll never do that."

In April 2009, Jobs underwent a liver transplant at Methodist University Hospital Transplant Institute in Memphis, Tennessee. Jobs's prognosis was described as "excellent".