OBJECTIVE To test the hypothesis that the predictive value for risk of fatal ischaemic heart disease associated with Lewis phenotypes depends on the level of leisure time physical activity.

DESIGN Prospective study controlling for alcohol, tobacco, serum cotinine, blood pressure, body mass index, serum lipids, work related physical activity, and social class.

SETTING The Copenhagen male study, Denmark.

SUBJECTS 2826 white men aged 53–75 years without overt cardiovascular disease; 266 (9.4%) had the Le(a−b−) phenotype.

MAIN OUTCOME MEASURE Incidence of death from ischaemic heart disease during 11 years.

RESULTS 107 men died of ischaemic heart disease. Among men with a low level of leisure time physical activity (⩽ 4 hours/week moderate or ⩽ 2 hours/week more vigorous activity), being Le(a−b−) was associated with an increased risk of having a fatal ischaemic heart disease event compared with men with other Lewis phenotypes (relative risk (RR) 2.7, 95% confidence interval (CI) 1.4 to 5.2; p < 0.01). Among men with a high level of leisure time physical activity, the RR associated with being Le(a−b−) was 1.3 (95% CI 0.5 to 3.1; NS). Compared with all other alternatives tested, being Le(a−b−) and having a low level of leisure time physical activity was associated with an RR of 3.2 (95% CI 1.7 to 5.8; p < 0.001). As a point estimate and adjusted for confounding variables, among men with low leisure time physical activity the attributable risk associated with Le(a−b−) was 12%—that is, assuming that all sedentary men had phenotypes other than Le(a−b−), 12% of all fatal ischaemic heart disease events would not have occurred. The corresponding point estimate among those more active was 2%.

CONCLUSIONS The excess risk of fatal ischaemic heart disease in middle aged and elderly men with the Le(a−b−) phenotype is strongly modified by leisure time physical activity. Public health and clinical implications may be important in populations with a predominantly sedentary lifestyle and in a high proportion of men with the Le(a−b−) phenotype.