Polydrug abuse, including the abuse of cocaine + heroin combinations (or 'speedballs') is an increasingly significant problem. The use of genetically defined populations of mice has the potential to add considerably to the study of polydrug abuse. Balb/cByJ (Balb/c) mice have been shown to self-administer opiates, but not cocaine, therefore these mice were chosen for the initial characterization of intravenous self-administration of cocaine + heroin combinations. Mice were implanted with chronic indwelling jugular catheters and given the opportunity to self-administer heroin, cocaine or heroin + cocaine combinations. Heroin was self-administered, while, under the same conditions, none of the mice tested acquired cocaine self-administration. However, heroin + cocaine combinations were self-administered in naive mice as well as in mice that had failed to self-administer cocaine alone. The heroin + cocaine combination dose-effect curve resembled the heroin dose-effect curve. It is hypothesized that heroin may interact with effects of cocaine that function to limit self-administration in Balb/c mice, facilitating the acquisition and maintenance of self-administration of cocaine + heroin combinations.