Reeve suffered from asthma and allergies since childhood. At age sixteen, he began to suffer from alopecia areata, a condition that causes patches of hair to fall out from an otherwise healthy head of hair. Generally he was able to comb over it and often the problem disappeared for long periods of time. Later in life, the condition became more noticeable and he shaved his head. He had experienced several illnesses, including Infectious mononucleosis and malaria. He suffered from mastocytosis, a blood cell disorder. More than once he had a severe reaction to a drug. In Kessler, he tried a drug named Sygen which was theorized to help reduce damage to the spinal cord. The drug caused him to go into anaphylactic shock and his lungs shut down. He believed he had an out-of-body experience and remembered saying, "I'm sorry, but I have to go now", before it occurred. In his autobiography, he wrote, "and then I left my body. I was up on the ceiling...I looked down and saw my body stretched out on the bed, not moving, while everybody—there were fifteen or twenty people, the doctors, the EMTs, the nurses—was working on me. The noise and commotion grew quieter as though someone were gradually turning down the volume." After receiving a large dose of epinephrine, he woke up and was able to stabilize later that night.
In 2003 and 2004, Reeve fought off a number of serious infections believed to have originated from the bone marrow. He recovered from three that could have been fatal. In early October 2004, he was being treated for a pressure wound that was causing a systemic infection called sepsis, a complication that he had experienced many times before. On October 9, Reeve felt well and attended his son Will's hockey game. That night, he went into cardiac arrest after receiving an antibiotic for the infection. He fell into a coma and was taken to North Westchester Hospital in Mount Kisco, New York. Eighteen hours later, on October 10, 2004, Reeve died of heart failure at the age of 52. His doctor, John McDonald, believed that it was an adverse reaction to the antibiotic that caused his death.