We know that the symptoms of PSP are caused by a gradual deterioration of brain cells in a few specific areas in the brain, mainly in the region called the brainstem. One of these areas, the substantia nigra, is also affected in Parkinson's disease, and damage to this region of the brain accounts in part for the motor symptoms that PSP and Parkinson's have in common.

Scientists do not fully know what causes these brain cells to degenerate, but it is known that a hallmark of the disease is the accumulation of an abnormal protein called tau. There is no evidence that PSP is contagious, and genetic factors have not been implicated in most individuals. No ethnic or racial groups have been affected more often than any others, and PSP is no more likely to occur in some geographic areas than in others.

There are, however, several theories about PSP's cause. One possibility is that an unconventional virus-like agent infects the body and takes years or decades to start producing visible effects. Another possibility is that random genetic mutations, of the kind that occur in all of us all the time, happen to occur in particular cells or certain genes, in just the right combination to injure these cells. A third possibility is that there is exposure to some unknown chemical in the food, air, or water which slowly damages certain vulnerable areas of the brain. This theory stems from a clue found on the Pacific island of Guam, where a common neurological disease occurring only there and on a few neighboring islands shares some of the characteristics of PSP, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (Lou Gehrig's disease). Its cause is thought to be a dietary factor or toxic substance found only in that area.

Another possible cause of PSP is cellular damage caused by free radicals, reactive molecules produced continuously by all cells during normal metabolism. Although the body has built-in mechanisms for clearing free radicals from the system, scientists suspect that, under certain circumstances, free radicals can react with and damage other molecules. A great deal of research is directed at understanding the role of free radical damage in human diseases.