Abstract We have investigated the potentiating action of cAMP on L-currents of rat chromaffin cells and the corresponding increase of Ca 2+-evoked secretory responses with the aim of separating the action of cAMP on Ca 2+ entry through L-channels and the downstream effects of cAMP/protein kinase A (PKA) on exocytosis. In ω-toxin-treated rat chromaffin cells, exposure to the permeable cAMP analog 8-(4-chlorophenylthio)-adenosine 3′,5′-monophosphate (pCPT-cAMP; 1 mM, 30 min) caused a moderate increase of Ca 2+ charge carried through L-channels (19% in 10 mM Ca 2+ at +10 mV) and a drastic potentiation of secretion (∼100%), measured as membrane capacitance increments (Δ C). The apparent Ca 2+ dependency of exocytosis increased with pCPT-cAMP and was accompanied by 83% enhancement of the readily releasable pool of vesicles with no significant change of the probability of release, as evaluated with paired-pulse stimulation protocols. pCPT-cAMP effects could be mimicked by stimulation of β 1-adrenoreceptors and reversed by the PKA inhibitor H89, suggesting strict PKA dependence. For short pulses to +10 mV (100 ms), potentiation of exocytosis by pCPT-cAMP was proportional to the quantity of charge entering the cell and occurred independently of whether L, N, or P/Q channels were blocked, suggesting that cAMP acts as a constant amplification factor for secretion regardless of the channel type carrying Ca 2+. Analysis of statistical variations among depolarization-induced capacitance increments indicates that pCPT-cAMP acts downstream of Ca 2+ entry by almost doubling the mean size of unitary exocytic events, most likely as a consequence of an increased granule-to-granule rather than a granule-to-membrane fusion.