Maximal L-glutamate/glycine-evoked currents were inhibited by ethanol in Xenopus laevis oocytes expressing recombinant heteromeric NMDA receptors consisting of NR1-NR2A, NR1-NR2B, and NR1-NR2C subunit combinations. Concentration-dependent inhibition was observed at ethanol concentrations of 50 mM both in Ca2+-containing and Ca2+-deficient, Ba2+-containing Mg2+-free media. The NR1-NR2C channels were slightly less sensitive to ethanol inhibition than the other heteromeric channels in Ca2+-deficient, Ba2+-containing medium. The inhibition was unaffected by the clamping-voltage and by a mutaion [NR1-NR2A(N595Q)] that prevents the Mg2+-blockade of the channels, indicating that the mechanism of action of ethanol differs from that of Mg2+. The results are consistent with the hypothesis that the NMDA receptor subtypes can mediate many behavioural actions of ethanol.