The relationship between physical activity and acute myocardial infarction (AMI) was examined in a case-control study conducted in Italy in 1988 to 1989 within the framework of the GISSI-2 trial of streptokinase versus alteplase and heparin versus no heparin in the treatment of AMI. A total of 916 case patients admitted to coronary care units from various Italian regions for AMI were interviewed. Control subjects were 1106 patients admitted to the same network of hospitals for a broad spectrum of acute diseases not related to known or potential risk factors for myocardial infarction. Among various types of physical activity (occupational activity, walking, stair climbing, and sport and leisure-time physical activity), occupational physical exercise emerged as the most protective. Multivariate odds ratios (ORs) were 1.4 (95% confidence interval (CI), 1.0 to 2.0) and 1.6 (95% CI, 1.2 to 2.1) for the two lowest levels of occupational physical activity. The trends of increasing risk with decreasing activity were consistent, although less strong, when other types of activity were considered. The protection conveyed by occupational physical activity was similar across various strata of sex, age, education, smoking habits, and diabetes, and was not explained by serum cholesterol, body weight, or hypertension. This study therefore confirms that low physical activity is an indicator of subsequent risk of AMI.