Tobacco smoking is one of the principal risk factors of peripheral arterial disease (PAD); cholesterol level has a lesser impact. The effect of leisure-time physical activity (LTPA) has not been studied in depth. The aim of this study was to determine the relative effects of smoking, total cholesterol, and leisure-time physical activity on blood flow parameters in the lower extremities of healthy middle-aged men with no prior symptoms or diagnosis of PAD. The authors examined 130 men, aged 40-65 years, free of known arterial disease and hypertension. The men had either a total cholesterol concentration of < 5.7 or > 7.0 mmol/L, and were either smokers or nonsmokers. LTPA was addressed by a questionnaire. Ankle-brachial index (ABI) was calculated and Doppler examination of the femoral artery was performed before and after an exercise test. Tobacco smoking related significantly to abnormal ABI and Doppler results (odds ratio [OR] 2.42) while the total cholesterol level did not. LTPA had a favorable effect (OR 0.51). Abnormal ABI response was greatest in smokers with high total cholesterol (p < 0.01). Tobacco smoking is a significant risk factor for abnormal ABI response and blood flow abnormalities in healthy men. Regular physical activity has a measurable protective effect. An abnormal ABI suggests early atherosclerosis and indicates risk factor assessment and physician intervention.