Modulation of excitatory postsynaptic currents by histamine was examined using whole cell recording methods in the CA1 region of slices of rat hippocampus. Histamine affected the N-methyl-D-aspartate (NMDA) component of the synaptic current in a pH-dependent manner: at lowered pH (7.2) it enhanced the NMDA-mediated synaptic currents while at raised pH (7.6) it reduced them. At a pH of 7.4 there was no significant action of histamine. Histamine failed to alter the non-NMDA component of the synaptic current. These results indicate that histamine acts at a postsynaptic site to modulate NMDA mediated synaptic currents in a pH dependent manner. This mechanism may have important implications for the pathophysiology of shifts in extracellular pH.