The primary objective of the study was to determine the effect of levodopa (LD) on human substantia nigra. The study included patients seen at the Movement Disorder Clinic, Saskatoon over a 32 year period. The evidence provided is based on epidemiological observations of 934 consecutive Parkinson syndrome (PS) patients assessed during 22 years and detailed studies of six patients including two autopsies. Life expectancy increased significantly with LD therapy. The prolonged survival was evident when the patients were treated during early stage of the illness. One parkinsonian patient with substantia nigra (SN) pathology who was extensively studied for 30 years, revealed significant slowing of the disease progression while on LD. Three essential tremor patients who received 24 kg (26 years), 22 kg (21.5 years), and 8.5 kg (12.5 years) LD respectively, had no evidence of PS and one autopsy revealed normal SN. Two dopa-responsive dystonia patients who received LD 3 kg (11 years) and 17 kg (29 years) each had no evidence of PS and one autopsy revealed normal number of SN neurons. These observations indicate that LD is not toxic to human SN and are consistent with salutary effect of the drug on the SN in Parkinson's disease.