The pharmacology of a slowly inactivating outward current was examined using whole-cell patch clamp recordings in CA3 pyramidal cells of guinea pig hippocampal slices. The current had a low activation threshold (about -60 mV) and inactivated slowly (time constant of 3.4 ± 0.5 s at -50 mV) and completely at membrane voltages depolarized to -50 mV. The slowly inactivating outward current was mainly mediated by K⁺ with a reversal potential close to the equilibrium potential for K⁺. The slowly inactivating outward current had distinct pharmacological properties: its time course was not affected by extracellular Cs⁺ (1 mM) or 4-AP (1-5 mM) - broad spectrum inhibitors of K⁺ currents and of inactivating K⁺ currents, respectively. The presence of extracellular Mn²⁺ (0.5-1 mM), which suppresses several Ca²⁺-dependent K⁺ currents, also did not affect the slowly inactivating outward current. The current was partially suppressed by TEA (50 mM) and was blocked by intracellular Cs⁺ (134 mM). In addition, intracellular QX-314 (5 mM), a local anesthetic derivative, inhibited this current. The slowly inactivating outward current with its low activation threshold should be operational at the resting potential. Our results suggest that the transient outward current activated at subthreshold membrane potentials in hippocampal pyramidal cells consists of at least three components. In addition to the well-described A- and D-currents, the slowest decaying component reflects the time course of a distinct current, suppressible by QX-314.