We studied the effects of serotonin (5-HT) on intrinsic and synaptic responses of hippocampal CA1 cells. The effects were partially mimicked by the 5-HT1A receptor agonist, 8-OH-DPAT, and prevented by the 5-HT1A receptor antagonist, NAN-190. Polysynaptic fast and slow inhibitory postsynaptic potentials (IPSPs) were reduced in amplitude by 60–70% following application of both 5-HT and 8-OH-DPAT. Monosynaptic fast IPSPs were reduced by 60% and slow IPSPs by 90% following application of both drugs. Since there is a temporal overlap of fast and slow IPSPs, the reduction in fast IPSPs could have arisen indirectly from the larger effect of 5-HT on slow IPSPs. To overcome this problem we blocked the slow IPSPs with new, potent GABA-B antagonists, but still observed a similar reduction in the fast IPSP with 5-HT and 8-OH-DPAT. However, the reductions in the fast IPSPs could also have arisen from the 5-HT-induced total conductance increases. Using single-electrode voltage clamp and intracellular K+ channel blockers we still observed similar changes. 5-HT and 8-OH-DPAT had no effect upon GABA-A-mediated currents evoked by iontophoretic GABA application to the dendrites or the soma of CA1 pyramidal cells, Putative inhibitory internuerons were hyperpolarized by 5-HT and their evoked EPSPs strongly reduced by 5-HT and 8-OH-DPAT. Our data indicate that 5-HT modulates fast and slow synaptic inhibition of principal cells using presynaptic mechanisms involving the inhibition of inhibitory interneurons.