Parkinson's disease (PD) is likely a result of both inherited and exogenous factors. In a study of 144 PD cases and 464 controls, we used PD family history as a surrogate for inherited PD susceptibility. Cases were more likely to report a first- or second-degree relative with PD: 16.0 vs. 4.3%; odds ratio (OR) = 4. 2; 95% confidence interval (CI) = 2.3-7.6. A PD family history was a greater risk factor for PD in subjects under age 70 (OR = 8.8; 95% CI = 3.4-22.8) compared with those over 70 (OR = 2.8; 95% CI = 1.3-6. 1) and in men (OR = 8.1; 95% CI = 3.4-19.2) compared with women (OR = 2.6; 95% CI = 1.1-6.0). We also tested whether a PD family history modified the effects of other PD risk factors. In subjects with a PD family history, occupational exposure to copper, lead or iron increased the risk for PD (OR = 3.0; 95% CI = 0.7-13.3), but this was not the case for those without a family history (OR = 1.1; 95% CI = 0.7-1.6). Ever smoking cigarettes was inversely associated with PD in those without a PD family history (OR = 0.6; 95% CI = 0.4-0.9), but was positively associated with PD in those with a PD family history (OR = 1.7; 95% CI = 0.5-5.9). In summary, our results suggest that a PD family history, and perhaps, therefore, an inherited susceptibility, confers a greater risk for PD in men and individuals under 70 years of age and may modify the effects of environmental risk factors for PD.