Levodopa is the most effective drug for symptomatic control of Parkinson syndrome (PS). We report a 22-year clinicopathological study of 59 PS cases. Of the entire group, 37 (63%) had an adequate trial on levodopa. Some improvement was noted on that drug in 24 (65%) cases. Improvement was seen in 94% of idiopathic Parkinson's disease cases as well as in all cases in which the pathology was characterized by neuronal loss in the substantia nigra without Lewy body inclusions. Improvement was also noted in 60% of patients with the dual pathology of idiopathic Parkinson's disease and Alzheimer's disease, and in one-third of early multiple system atrophy cases. We conclude that improvement on levodopa is a strong indication that the pathological basis of the parkinsonism is the damage to substantia nigra neurons. A favorable response to levodopa, however, is not an indication of idiopathic (Lewy body) Parkinson's disease.