The acute hemodynamic effects, long-term clinical efficacy, and safety of the oral angiotensin-converting enzyme inhibitor, captopril, were assessed in a multicenter cooperative study of 124 patients with heart failure resistant to digitalis and diuretics. The cardiac status of most patients was deteriorating prior to the study. Favorable acute hemodynamic effects consistently occurred with captopril. Maximal mean percentage increases in cardiac index, stroke index, and stroke work index were, respectively, 35%, 44%, and 34%. Systemic and pulmonary vascular resistances were each decreased by approximately 40%, as were the filling pressures of the right and left heart. Infusion of nitroprusside in some of the same patients to an end point of a pulmonary capillary wedge pressure of 12 to 18 mm Hg (equivalent to that after captopril) revealed no significant difference in the effect of either drug on the other hemodynamic parameters. Recatheterization after 8 weeks of captopril therapy revealed sustained hemodynamic changes. Significant and sustained improvements in clinical status were observed in most patients as measured by changes in New York Heart Association (NYHA) functional classification and exercise tolerance times. Seventy-nine percent of patients for whom there were adequate NYHA class data improved. Twenty percent remained unchanged and 1% deteriorated. Those patients who had both pretreatment and post-treatment exercise stress testing exhibited a highly significant mean increase in exercise tolerance times of 34% (317 ± 32 seconds pretreatment to 425 ± 34 seconds, final measurement). There was no evidence of tachyphylaxis over an 18-month period. Survival rates at 6, 12, 18, and 24 months were 79%, 63%, and 58%, respectively. Cardiothoracic ratios showed a significant decrease from a mean of 0.60 to 0.57 at 2 months. All patients with hypokalemia at entry and all but one with hyponatremia normalized rapidly on captopril therapy. Captopril was generally well tolerated, although hypotension caused withdrawal of the drug in 6% of patients. The results suggest a useful role for captopril in heart failure.