There are environmental determinants and genetic susceptibility to coronary heart disease (CHD); however, identifying factors that modify genetic risk has been difficult. Evidence suggests that a common polymorphism in the hepatic lipase gene (LIPC-480C>T) may be related to susceptibility to CHD and that physical activity is a behavioral factor associated with CHD. This population-based prospective study in the San Luis Valley of Colorado investigated the role of the LIPC-480C>T polymorphism in predicting clinical CHD and the modifying effect of physical activity. Hispanics and non-Hispanic Whites (n = 966) were followed for 14 years (1984-1998); 91 CHD events occurred. The LIPC-480 TT genotype predicted an increase in CHD in both ethnic groups, and physical activity altered this relation. In the full cohort, the rate of CHD was significantly elevated among subjects with the high-risk genotype and normal levels of physical activity (hazard ratio = 2.58, 95% confidence interval: 1.39, 4.77) but was not elevated among those with the high-risk genotype who participated in vigorous physical activity (hazard ratio = 0.52, 95% confidence interval: 0.12, 2.19) (reference group: LIPC-480 CC/CT, normal physical activity). Thus, in this prospective cohort study, the LIPC-480 TT genotype increased susceptibility to CHD only in those subjects with normal levels of physical activity, not in those with the high-risk genotype who were vigorously active.