Transient inward currents (I ti) during oscillations of intracellular [Ca2+] ([Ca2+]i) in ventricular myocytes have been ascribed to Na/Ca exchange. We have investigated whether other Ca2+-dependent membrane currents contribute to I ti in single guinea-pig ventricular myocytes, by examining membrane currents during [Ca2+]i oscillations and during caffeine-induced Ca2+ release from the sarcoplasmic reticulum in the absence of Na+. Membrane currents were recorded during whole-cell voltage clamp and [Ca2+]i measured simultaneously with fura-2. In the absence of Na/Ca exchange, i.e., with Li+, Cs+ or N-methyl-D-glucamine (NMDG+) substituted for Na+, the cell could be loaded with Ca2+ by repetitive depolarizations to +10 mV, resulting in spontaneous [Ca2+]i oscillations. During these oscillations, no inward currents were seen, but instead spontaneous Ca2+ release was accompanied by a shift of the membrane current in the outward direction at potentials between −40 mV and +60 mV. This [Ca2+]i-dependent outward current shift was not abolished when NMDG+ was substituted for internal monovalent cations, nor was it sensitive to substitution of external Cl−. It was however, sensitive to the blockade of ICa by verapamil. These results suggest that the transient outward current shift observed during spontaneous Ca2+ release represents [Ca2+]idependent transient inhibition of I Ca. Similarly, during the [Ca2+]i transients induced by brief caffeine (10 mM) applications, we could not detect membrane currents attributable to a Ca2+-activated nonselective cation channel, or to a Ca2+-activated Cl− channel; however, transient Ca2+-dependent inhibition of I Ca was again observed. We conclude that neither the Ca2+-activated nonselective cation channel nor the Ca2+-activated Cl− channel contribute significantly to the membrane currents during spontaneous [Ca2+]i oscillations in guineapig ventricular myocytes. However, in the voltage range between −40 mV and +60 mV Ca2+-dependent transient inhibition of I Ca will contribute to the oscillations of the membrane current.