The Multiple Risk Factor Intervention Trial was a randomized clinical study to test whether a special-intervention (SI) program aimed at reducing serum cholesterol levels, blood pressure and cigarette smoking would prevent coronary heart disease (CHD) in middle-aged men. The main endpoint reported here is the percentage of participants experiencing first major CHD events (either nonfatal acute myocardial infarction [AMI] or CHD death) during 7 years of follow-up. This outcome was slightly less frequent in the 6,428 SI men than in the 6,438 men assigned to their usual source of care (UC). However, the relative difference--either 1% (95% confidence interval -17% to 16%) or 8% (95% confidence interval -5% to 20%), depending on how AMI was classified--was not statistically significant. Regression analyses within the SI and UC groups suggested that the cholesterol and cigarette smoking interventions reduced the number of first major CHD events: the associations between lowering the levels of these 2 factors and reductions in CHD rates were significant (p less than 0.001) and of the anticipated magnitude. A similar analysis of antihypertensive treatment in the SI group revealed no favorable association between lowering blood pressure and CHD rate, and other subgroup comparisons suggested that a mixture of beneficial and adverse effects may underlie this finding. Thus, the nonsignificant overall UC/SI contrast in CHD rates may reflect a combination of the expected beneficial effects of the cholesterol and smoking interventions with unexpected heterogeneous effects of the antihypertensive intervention. Seven of 8 other prespecified cardiovascular endpoints occurred less frequently among SI than among UC men, the difference being nominally significant (p less than 0.05) for angina pectoris, congestive heart failure and peripheral arterial disease.