Among promising biological markers proposed for Parkinson's disease (PD) and other disorders related to Lewy bodies, plasma alpha-synuclein assay has provided conflicting results mainly owing to the various laboratory assay techniques used and protein forms assayed. In this observational and exploratory cross-sectional study, using an immunoenzymatic technique, we assayed and compared total plasma alpha-synuclein concentrations in 69 patients with PD and 110 age-matched healthy control subjects. Two previously unreported findings concerned gender. First, plasma alpha-synuclein concentrations measured in the more advanced parkinsonian disease stages decreased in men, but not in women. Second, again only in men, plasma alpha-synuclein concentration was associated with cognitive impairments, hallucinations, and sleep disorders. These findings underline the gender-related differences in parkinsonian patients and indicate plasma alpha-synuclein expression as a potential biological marker for PD progression in men.