Although it is well established that methadone can be an effective treatment for opiate addiction, it is not clear how methadone maintenance affects cocaine use and cravings in individuals who self-administer both opiates and cocaine. In our attempt to explore the effect of methadone maintenance on the effects of cocaine, we first assessed the locomotor stimulatory effects of cocaine in rats maintained on methadone (0, 10, 20, or 30 mg/kg/day, via osmotic minipumps). Chronic methadone elevated baseline locomotion in a dose-dependent manner and did not reduce the direct stimulatory effects of cocaine (5 mg/kg). We then investigated the effects of the highest methadone maintenance dose (30 mg/kg/day) on heroin and cocaine seeking in extinction, and when it was precipitated by exposure to heroin, cocaine, or foot-shock stress in rats trained to self-administer both drugs in the same experimental context (heroin 0.05 mg/kg/inf; cocaine 0.5 mg/kg/inf, eight 3-h sessions each). In tests of reinstatement, rats responded selectively on the appropriate drug-associated lever after priming injections of heroin (0.25 mg/kg) or cocaine (20 mg/kg). Methadone maintenance blocked both cocaine- and heroin-induced reinstatement, but not stress-induced reinstatement, which was not lever selective. These results suggest that although methadone maintenance may not reduce the direct stimulatory effects of cocaine, it has the potential to reduce both spontaneous and cocaine-primed cocaine-seeking behavior.