On 7 March 2005, he was again hospitalized with a lung infection. Rainier was moved to the hospital's intensive care unit on 22 March. One day later, on 23 March, it was announced he was on a ventilator, suffering from renal and heart failure. On 26 March, the palace reported that despite intensive ongoing efforts to improve the prince's health, he was continuing to deteriorate; however, the following day, he was reported to be conscious, his heart and kidney conditions having stabilized. His prognosis remained "very reserved".
On 31 March 2005, following consultation with the Crown Council of Monaco, the Palais Princier announced that Rainier's son, Hereditary Prince Albert, would take over the duties of his father as regent since Rainier was no longer able to exercise his royal functions.
On 1 April 2005, the Palace announced that Rainier's doctors believe his chances of recovery were "slim". On 6 April, Prince Rainier died at the Cardiothoracic Centre of Monaco at 6:35 am local time at the age of 81. He was succeeded by his only son, who became Prince Albert II. He was buried on 15 April 2005 beside his wife, Princess Grace, at the Cathedral of Our Lady Immaculate, the traditional burial place of princes and princesses of Monaco, and the place where Prince Rainier and Princess Grace had been married in 1956. Because his death occurred shortly after that of Pope John Paul II, Rainier's death was overshadowed in the media.