Antagonism of the NMDA receptor with MK-801 is considered to be an effective pharmacologic manipulation to prevent the development of sensitization effects to drugs such as cocaine. The present study investigated this issue by comparing the behavioral response of separate groups of rats to three treatment cycles of either saline, 0.1 mg/kg MK-801, 10 mg/kg cocaine, or combined MK-801-cocaine (0.1/10 mg/kg). The treatments were spaced 1 week apart and were preceded by two nondrug baseline tests. In the first test cycle, the four groups had equivalent activity levels in the two nondrug tests. In the first drug test only the MK-801-cocaine group exhibited hyperactivity. By the third drug test, the MK-801-cocaine group exhibited an enhanced hyperactivity and the MK-801 group became hyperactive. Thus, behavioral drug sensitization developed but only with groups treated with MK-801. Antagonism of the NMDA receptor under some circumstances can be a highly effective treatment for the induction of behavioral sensitization effects.