The relation of self-selected leisure-time physical activity (LTPA) to first major coronary heart disease (CHD) events and overall mortality was studied in 12 138 middle-aged men participating in the Multiple Risk Factor Intervention Trial. Total LTPA over the preceding year was quantitated in mean minutes per day at baseline by questionnaire, with subjects classified into tertiles (low, moderate, and high) based on LTPA distribution. During seven years of follow-up, moderate LTPA was associated with 63% as many fatal CHD events and sudden deaths, and 70% as many total deaths as low LTPA (P<.01). Mortality rates with high LTPA were similar to those in moderate LTPA; however, combined fatal and nonfatal major CHD events were 20% lower with high as compared with low LTPA (P<.05). These risk differentials persisted after statistical adjustments for possible confounding variables, including other baseline risk factors and Multiple Risk Factor Intervention Trial group assignments. It is concluded that LTPA has a modest inverse relation to CHD and overall mortality in middle-aged men at high risk for CHD.