Interactions between the benzodiazepine derivatives, diazepam and oxazepam, and the narcotic analgesics, morphine and methadone, were evaluated on locomotor activity and in the tail-flick and hot-plate tests for analgesia in the mouse. The dose-related stimulation of locomotor activity by morphine was reduced by diazepam and oxazepam at doses which alone had no effect on locomotor activity. However, only oxazepam reduced the dose-related stimulation of locomotor activity by methadone. The observed decreases produced by diazepam and oxazepam were comparable in magnitude to those produced by naloxone. Stimulation of locomotor activity by d-amphetamine was not affected by either diazepam or oxazepam. Dose-response curves for locomotor activity were also determined with morphine and methadone administered intraventricularly. As before, diazepam and naloxone given i.p. decreased the stimulation of locomotor activity produced by morphine, but only naloxone affected methadone-stimulated locomotor activity. Neither diazepam, oxazepam nor naloxone reduced the brain or plasma levels of 3H-morphine or 3H-methadone. In contrast to the results on locomotor activity, neither of these benzodiazepines significantly modified the dose-response curves of morphine or methadone in either test for analgesia. The mechanisms involved in the observed interactions on locomotor activity may be related to the influences of benzodiazepines and narcotic analgesics on motor efferent pathways summating in such a manner as to interfere with the ability of the mice to locomote. The present results demonstrate that prominent interactions occur between members of the benzodiazepine and narcotic analgesic classes; these interactions are dependent upon both the specific combination of drugs administered and upon the test procedure.