Caffeine consumption is associated with a reduced risk of Parkinson's disease in men but not in women. This gender difference may be due to an interaction between caffeine and use of postmenopausal estrogens. The authors prospectively assessed the relation between coffee consumption and Parkinson's disease mortality among participants in the Cancer Prevention Study II, a cohort of over 1 million people enrolled in 1982. Causes of deaths were ascertained through death certificates from January 1, 1989, through 1998. Parkinson's disease was listed as a cause of death in 909 men and 340 women. After adjustment for age, smoking, and alcohol intake, coffee consumption was inversely associated with Parkinson's disease mortality in men (p(trend) = 0.01) but not in women (p = 0.6). In women, this association was dependent on postmenopausal estrogen use; the relative risk for women drinking 4 or more cups (600 ml) of coffee per day compared with nondrinkers was 0.47 (95% confidence interval: 0.27, 0.80; p = 0.006) among never users and 1.31 (95% confidence interval: 0.75, 2.30; p = 0.34) among users. These results suggest that caffeine reduces the risk of Parkinson's disease but that this hypothetical beneficial effect may be prevented by use of estrogen replacement therapy.