Rats were housed after weaning in isolation, with a same-sex sibling, or in a group in an enriched environment for 60 days. Then, subjects were trained to consume all of their fluids during a daily 2-h drinking session, habituated to drinking solutions of both d-amphetamine sulfate and sodium barbital, and then given a choice between drinking water, the stimulant amphetamine and the depressant barbital. Drug choice was affected by both sex and previous housing condition. Males raised in social isolation preferred the stimulant, while females raised in isolation preferred the depressant. Both males and females raised in enriched environments expressed no drug preference, and had the lowest overall drug intake. These results suggest that individual differences in rates of initiation, choice of abusing agent, and maintenance of drug self-administration may be partially determined by pre-existing differences in central nervous system functioning due to early experiences. Differential early experience, particularly the stress of social isolation, can influence drug self-administration behavior, but the effect may be sex-dependent.