Hypothermia and motor impairment (tilt-plane test) were used to assess whether N-methyl-D-aspartate (NMDA) receptors play a role in the development of rapid tolerance to ethanol, i.e., tolerance to a second dose of ethanol given 24 h after the effect of the first dose of ethanol had disappeared. Results showed that (+)-MK-801 and ketamine blocked the development of rapid tolerance to ethanol on both tests. Since these drugs did not modify blood or brain alcohol levels in any of the groups, the blockade of ethanol rapid tolerance cannot be attributed to changes in pharmacokinetics of ethanol. These data suggest that the role of NMDA receptors in ethanol tolerance may be similar to their role in memory and learning, involving a facilitation of transmission in certain synapses.