The effects of heroin and cocaine administered alone or in combination were examined in rats trained to discriminate either heroin (0.56 mg/kg IP; n = 6) or cocaine (5.6 mg/kg IP; n = 6) from saline. Heroin (0.032–1.8 mg/kg) substituted completely for the heroin training stimulus in all six heroin-trained rats, but failed to substitute for cocaine in any of the cocaine-trained rats. Cocaine (0.1–32 mg/kg) substituted completely for the cocaine training stimulus in all six cocaine-trained rats, and substituted for heroin in two of six heroin-trained rats. The opioid antagonist naltrexone (0.01–1.0 mg/kg) antagonized the discriminative stimulus effects of heroin, but naltrexone at doses up to 10 mg/kg had no effect on the discriminative stimulus effects of cocaine. The dopamine receptor antagonist flupenthixol (0.032–0.56 mg/kg) attenuated the discriminative stimulus effects of heroin and completely blocked the discriminative stimulus effects of cocaine. When heroin–cocaine combinations were administered to the heroin-trained rats, cocaine (1–5.6 mg/kg) did not significantly alter the mean heroin dose–effect curve. Similarly, in the cocaine-trained rats, heroin (0.1–0.56 mg/kg) did not significantly alter the mean cocaine dose–effect curve. These results suggest that combinations of heroin and cocaine usually produce discriminative stimulus effects similar to either heroin or cocaine alone.