In a prospective, population-based cohort study among 5,920 participants aged 55 years or older, we observed that the TT variant of the methylenetetrahydrofolate reductase C677T polymorphism is associated with an increased risk for Parkinson's disease in smokers. Both smoking and the TT genotype are known to induce hyperhomocystinemia, and synergistic effects on homocysteine levels have been reported. Increased plasma levels of homocysteine through direct neurotoxic effects might accelerate the selective dopaminergic cell death underlying Parkinson's disease. Our findings support the hypothesis that homocysteine plays a role in the pathogenesis of Parkinson's disease.