Summary The effects of different concentrations of caffeine on the electrical and mechanical events of ventricular myocardial fibers of the dog were studied in vitro under conditions that alter cellular calcium. Caffeine was found to: (a) increase the contractile force quickly and then slowly in a dose-dependent manner, causing contracture only at high concentrations; (b) shift to more positive values and shorten the plateau, slow the final phase III repolarization, and cause a slow return of potential to the resting value during diastole at high concentrations; (c) increase the magnitude but retard the relaxation of the twitch; (d) cause these effects independently of α- or β-adrenergic mechanisms; (e) shift the plateau to more negative values in the absence of calcium; (f) shift the plateau of the slow response action potentials to more positive values and increase the contractile force without prolonging the late phase III in high K; (g) induce less pronounced effects in the presence of local anesthetics or tetrodotoxin; (h) still increase force in the presence of manganese, verapamil, and ryanodine; (i) induce more pronounced effects in the presence of strophantidin; and (j) retard the fall in contractile force on exposure to zero calcium. It is concluded that caffeine, in addition to and as a consequence of other actions, enhances cellular calcium, which in turn is responsible for some of the electrical and mechanical effects of caffeine.