Objective: An inversion polymorphism of approximately 900kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case-control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson's disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings. Methods: We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the H1 and H2 clades. We also analyzed four SNPs that define subhaplotypes within H1 previously reported to associate with PD or other neurodegenerative disorders. Results: After adjusting for age, sex, and site, we observed a robust association between the H1/H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25-1.69; p = 8 × 10-7). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no significant difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes. Interpretation: Our data provide strong evidence that the H1 clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD.