Background: A polymorphism (G to A transition) in intron 13 of the mitochondrial enzyme monoamine oxidase B (MAOB) gene may modify, alone or by interacting with the catechol-O-methyltransferase (COMTLL) genotype (low enzymatic activity), the risk of idiopathic PD. Also, the association between never smoking and PD risk may be present only in people with the MAOB G allele. Methods: The authors studied two ongoing prospective cohorts-the Nurses' Health Study (121,700 women aged 30 to 55 in 1976) and the Health Professionals' Follow-up Study (51,529 men aged 40 to 75 in 1986). They identified new PD cases through 1996, selected random control subjects matched on age and study cohort, and obtained DNA samples from blood or buccal smears from 85% of the eligible cases and 84% of the control subjects. They included genotypes from 214 cases and 449 control subjects, all Caucasian. Results: The odds ratio of PD was 1.2 (95% CI 0.9, 1.7) for MAOB genotypes G/GG/GA compared with genotypes A/AA, and 1.1 (0.7, 1.8) for COMT genotypes LL compared with HH. The odds ratio (95% CI) was 1.7 (0.7, 3.9) for those with MAOB G/GG and COMTLL genotypes compared with those with MAOB A/AA and COMTHH. There was a strong association between never smoking and PD risk in all groups defined by MAOB and COMT genotypes. Conclusion: The findings do not support a major role of the MAOB intron 13 polymorphism in the development of PD, either by itself or by interacting with smoking.