α-Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of α-synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the α-synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case–control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the α-synuclein gene. Several markers within the 3′-block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5′-block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age. Ann Neurol 2005;57:535–541