Using whole-cell patch-clamp recording of acutely isolated rat hippocampal CA1 neurons, we studied the state-dependent cross-inhibition between anionic GABA(A) and glycine (Gly) ionotropic receptors. Co-application of relatively high concentrations of GABA and Gly produced a total current (IGABA + Gly) much smaller than the linear summation of the two individual responses. The mutual inhibition between IGABA and IGly was voltage-independent. However, no current inhibition was observed with co-application of low concentrations of these two agonists. The hippocampal neurons lacking Gly response (IGly) showed no current inhibition with GABA current (IGABA), whereas the neurons losing GABA response (IGABA) (after complete rundown of IGABA) showed no current inhibition with IGly. The current inhibition was also absent in the presence of Gly or GABA(A) receptor antagonists, strychnine or bicuculline, respectively. The results indicate that cross-inhibition between GABA(A) and Gly receptors is state-dependent and a direct receptor-receptor interaction might enable the cross-inhibition to occur.