Objectives: This study sought to compare the influence of changes in systolic interval on the negative inotropic effects of metoprolol, sotalol, and verapamil in patients with ischemic heart disease. Background: The long-term symptomatic and prognostic effects of antiarrhythmic agents are not easily predicted on the basis of acute hemodynamic actions at rest, but may be unmasked during tachycardia. However, this has not been studied extensively in vivo. Methods: The force-interval relationship of the intact human left ventricle was examined before and 10 min after intravenous bolus administration of the negatively inotropic agents metoprolol, sotalol, or verapamil in patients undergoing diagnostic cardiac catheterization. Results: All three drugs similarly reduced maximal rate of increase of left ventricular pressures (LV+dP/dtmax) by approximately 10%, but diversely modified the force-interval relationship. The parameter c (the reduction in LV+dP/dtmax of a fixed premature stimulus on mechanical restitution) was significantly reduced by metoprolol (by 9 ± 4%, p < 0.05), was increased by verapamil (by 6 ± 2%, p < 0.05), and was not significantly changed by sotalol. Similarly, metoprolol had a minimal effect on the extent of frequency potentiation, whereas sotalol and verapamil attenuated frequency potentiation (the relative response to 10 s of rapid pacing was 1.19 ± 0.58-fold, 0.07 ± 0.35-fold, and 0.03 ± 0.17-fold of the baseline response after 10 min of metoprolol, sotalol, or verapamil, respectively). Conclusions: These results show that the negative inotropic effects of metoprolol are attenuated and those of verapamil are accentuated at short cycle lengths; sotalol is intermediate between the two. These properties may contribute to the relative safety of these agents in patients prone to hemodynamic deterioration during sustained tachycardia.