The effects of subcutaneous injections of methadone hydrochloride (0.75mg, 1.5mg and 2.5mg/kg) on lever pressing maintained by fixed ratio schedules of reinforcement were examined in C57BL/6J and DBA/2J mice. Response output over a 30 min session decreased as a function of increasing drug dose when reinforcement was delivered for every 5 responses. Increasing the response to reinforcement ratio from 5 to 20 in a second experiment doubled and nearly quadrupled responding by DBA and C57 mice, respectively. Injecting animals maintained on this schedule with methadone reduced responding to the same extent as that observed in the first experiment when response rates were lower. Hence, these experiments provide no support for the effect of methadone being rate-dependent. In both experiments methadone disrupted responding of DBA more than that of C57 mice. This finding is consistent with a previous report that other narcotic analgesics were more potent analgesics for DBA than for C57 mice. From these studies it appears that the opposite changes in locomotor activity upon an exposure to narcotic analgesics does not generalize to behavior under control of reinforcing stimuli; and that both the effects obtained in the present study and the analgesic action are dissociated from the effects of these drugs on locomotor activity.