The mechanism by which afterload reduction increases left ventricular stroke volume while decreasing left ventricular filling pressure has not previously been established. In 15 patients with severe congestive heart failure due to ischemic or idiopathic dilated cardiomyopathy, absolute ventricular volume, ejection fraction and total stroke volume from radionuclide ventriculography were compared with thermodilution stroke volume before and after intensive afterload reduction with vasodilators and diuretics titrated to hemodynamic goals. After 48 to 72 hours, pulmonary artery wedge pressure decreased from 32 +/- 8 to 16 +/- 4 mm Hg and systemic vascular resistance from 1,960 +/- 700 to 1,200 +/- 400 dynes s cm-5. End-diastolic volume decreased from 390 +/- 138 to 301 +/- 126 ml (p less than 0.01) and end-systolic volume from 316 +/- 127 to 241 +/- 111 (p less than 0.01). Ejection fraction did not change and total stroke volume decreased from 74 +/- 22 to 59 +/- 20 ml (p less than 0.01). Simultaneous forward stroke volume by thermodilution increased from 37 +/- 14 to 52 +/- 14 ml (p less than 0.01), and forward fraction increased from 0.55 +/- 0.40 to 0.96 +/- 0.42. Intensive reduction of ventricular filling pressure and systemic vascular resistance decreased total ventricular stroke volume by 20% but increased forward stroke volume by 40%. The major effect of intensive afterload reduction for severe congestive heart failure may be the reduction of ventricular volume and mitral regurgitation.