Parkinson's disease has been associated with defects in oxidative phosphorylation (Oxphos). We analyzed mitochondria isolated from muscle biopsies of 6 patients with Parkinson's disease for deficiencies in Oxphos enzymes and for mutations in the mitochondrial DNA. Oxphos enzyme assays were compared to the 5 to 95% confidence intervals from 16 control subjects. Four patients had complex I defects, whereas 1 patient had a complex IV defect. A genetic basis for Parkinson's disease was suggested by the presence of affected relatives of 2 patients with Parkinson's disease. Known pathological mitochondrial DNA mutations (insertion-deletions or point mutations) were not found. We conclude that Parkinson's disease is a systemic disorder of Oxphos, probably of a complex genetic etiology. Premature cell death in the nigrostriatal dopamine pathway could be due to energetic impairment and accentuated free radical generation caused by an Oxphos defect.