Objectives Men with high physical work demands have elevated cardiovascular strain, which may lead to enhanced atherosclerosis. Theoretically, the impact of risk factors for ischaemic heart disease (IHD) may thus depend on physical work demands. The authors investigated this hypothesis. Design Prospective 30-year follow-up. Setting The Copenhagen Male Study. Participants 5249 gainfully employed men aged 40-59 years; 311 men with cardiovascular disease/diabetes were excluded. Primary and secondary outcome measures IHD and all-cause mortality. Results 579 men (11.8%) died due to IHD and 2628 (53.7%) from all-cause mortality. Similarities and differences in risk predictors were found between men with low (n=1219), medium (n=2636) and high (n=846) physical work demands. After control for potential confounders, high physical fitness conferred a reduced risk of IHD mortality only among men with high physical work demands (HR: 0.48, 95% CI 0.24 to 0.96), a moderate/high level of leisure-time physical activity was associated with reduced risk of IHD mortality only among men with moderate and high physical work demands. High systolic blood pressure and smoking were risk factors in all groups. Similar, but less pronounced differences in risk factors for all-cause mortality between groups were found. Conclusions The risk factors for IHD and all-cause mortality, low physical fitness and low leisure-time physical activity are not identical for men with different physical work demands. Preventive initiatives for IHD should be tailored to the physical work demands.