Experiments were done using guinea pig sympathetic neurons dissociated from the stellate ganglia to establish whether calcium-induced calcium release (CICR) modulated action potential (AP) generation in mammalian neurons. Using measurements of intracellular calcium ([Ca2+]i) with the Ca2+-sensitive dye fluo-3, we demonstrated that 10 mM caffeine activated ryanodine receptors and caused a rise in [Ca2+]i both in Ca2+-containing and Ca2+-deficient solutions. We also demonstrated that combined treatment of caffeine and 1 µM thapsigargin or caffeine and 20 µM ryanodine blocked subsequent caffeine-induced elevations of [Ca2+]i. Treatment with thapsigargin, ryanodine or 200 µM Cd2+ to disrupt CICR decreased the latency to AP generation during 400 ms depolarizing current ramps using the perforated patch whole cell patch clamp in current clamp mode. Treatment with 500 µM tetraethylammonium also decreased the latency to AP generation during depolarizing current ramps in control cells, but not in cells pretreated with thapsigargin to deplete internal Ca2+ stores. In summary, we propose that an outward current, carried at least in part through BK channels, is activated by CICR at membrane voltages approaching the threshold for AP initiation and that this current opposed depolarizing current ramps applied to guinea pig sympathetic stellate neurons.