Reeve was paralyzed from the neck down in a May 1995 horse steeple jump competition. Despite the near-fatal accident, Reeve never gave up hope that he would walk again.
Reeve, who spent about $400,000 a year on health care, stunned the nation when he eventually was able to move the fingers on his left hand and the toes on his feet. He said he had been able to restart his motor skills with a form of therapy that used a combination of electrical muscle stimulation and repetitive motion exercises.
Last year, Reeve had surgery to have experimental electrodes implanted in his diaphragm, which extended his ability to breathe without a respirator.
He used his fame to win attention and funding for scientific study of disabilities such as his and to lobby for looser restrictions on stem cell research.
"I consider myself a spokesman for people who can't call the president or a senator or testify before Congress," Reeve said in a 1998 interview with The Associated Press.
Despite Reeve's progress, he still had to cope with life-threatening bouts with infections.
Last month, Reeve revealed in a Reader's Digest interview that he fought off three dangerous infections this year.
"The most recent was a blood infection caused by an abrasion on my left hip that I probably picked up one day when I was on the exercise bike," Reeve said in the interview. "It seemed benign but developed into strep. Then a lot of major organs shut down."
Born Sept. 25, 1952, in New York to journalist Barbara Johnson and writer and professor Franklin Reeve, Reeve began acting as a child and continued to perform professionally as he studied at Cornell University and then New York's Juilliard School of Performing Arts.
Reeve got his first show business break in 1976 when he played opposite Katharine Hepburn on Broadway in "A Matter of Gravity." He became a big-screen star in 1978 when he was cast in "Superman."
Reeve went on to star in several more movies before his accident, including "The Bostonians" in 1984 and "The Remains of the Day" in 1993.
Reeve restarted his acting career with a 1998 starring role in the TV remake of "Rear Window."
Reeve is survived by his wife, Dana Reeve, and their son, Will, 12; his parents, Franklin Reeve and Barbara Johnson; and two children from a previous relationship, Matthew, 25, and Alexandra, 21.