Acquisition and dose-related self-administration of heroin (H)/cocaine (C) combinations in C57BL/6 × SJL mice were studied in nose-poke or lever-press operant responding procedures. C57BL/6 × SJL mice readily acquired self-administration in both operant procedures with a combination of doses known to be ineffective when each drug was used alone (H:15 μg/kg and C:150 μg/kg per injection). Similar numbers of infusions were obtained under conditions of fixed-ratio (FR) 3 versus 1 for the nose-poke and lever-press responses, respectively. Dose–effect curves for heroin:cocaine combinations revealed a pattern corresponding to a leftward shift of the dose-response for intravenous cocaine self-administration. Curves were similar whether generated with 1 or 3 days of availability per dose, or including subjects that did not respond preferentially (>70% responses) to the hole or lever associated with drug delivery, along with those that did. Motor activity induced by a combination of low doses for each drug was examined (H: 0.375 mg/kg and C: 3.75 mg/kg, i.p.). Under these conditions, the combination of both drugs induced an initial cocaine-like stimulation of horizontal activity, in contrast to the tendency of heroin to decrease activity. It is concluded that heroin:cocaine combinations used in the present study had reinforcing effects in C57BL/6 × SJL mice, and produced a cocaine-like effect in the early part of drug-induced activity sessions, followed by a locomotor profile corresponding to the average of both drugs.