To elucidate the mechanisms by which the new bipyridine inotropic agent milrinone improves cardiac function, we examined multiple indexes of left ventricular diastolic function before and after administration of milrinone to patients with advanced (NYHA class III or IV) congestive heart failure. In 13 patients left ventricular pressure measurements were made with a micromanometer to permit assessment of peak negative dP/dt and the time constant of left ventricular isovolumic relaxation, T, before and after milrinone. In nine patients radionuclide ventriculographic studies were performed during left heart catheterization, allowing calculation of left ventricular peak filling rate, volumes, and the diastolic pressure-volume relationship before and after milrinone. After intravenous administration of milrinone, peak negative dP/dt increased (+18%; p < .01) and T decreased (-30%; p < .01), while heart rate increased by only 8% (87% ± 12 to 94 ± 15 beats/min; p < .01), left ventricular systolic pressure did not change, and mean aortic pressure fell by 11% (p < .01). Left ventricular peak filling rate increased (1.2 ± 0.6 to 1.7 ± 0.7 end-diastolic volumes/sec; p ≤ .02) despite a decrease in left ventricular filling pressure (mean pulmonary wedge pressure 27 ± 7 to 18 ± 9 mm Hg; p < .01). There was a fall in left ventricular end-diastolic pressure (28.6 ± 6 to 19 ± 7 mm Hg; p ≤ .01), with no significant change in left ventricular end-diastolic volume. This was associated with a downward shift in the left ventricular diastolic pressure-volume relationship in most cases. These changes in parameters of left ventricular diastolic relaxation and chamber distensibility after administration of milrinone suggest that improved diastolic function may contribute to the beneficial hemodynamic effect of milrinone in patients with congestive heart failure.