There is ample biochemical, pathological, and genetic evidence that the metabolism of -synuclein (-syn) plays a crucial role in the pathogenesis of Parkinson disease (PD). To examine whether quantification of -syn in cerebrospinal fluid (CSF) is potentially informative in the diagnosis of PD, we developed a specific ELISA system and measured the concentration of -syn in CSF from 33 patients with PD (diagnosed according to UK PD Society Brain Bank criteria) and 38 control subjects including 9 neurologically healthy individuals. We found that PD patients had significantly lower -syn levels in their CSF than the control groups (p < 0.0001) even after adjusting for gender and age. Age was independently associated with lower -syn levels. Logistic regression analysis showed that reduction in CSF -syn served as a significant predictor of PD beyond age and gender alone (area under ROC curve, c = 0.882). Furthermore, we observed a close inverse correlation between -syn levels in CSF and assigned Hoehn and Yahr score in this cohort of 71 living subjects (p < 0.0001), even after adjusting for age. These findings identify in the quantification of -syn from CSF a potential laboratory marker to aid the clinical diagnosis of PD.