Variations in dietary constituents such as carbohydrate are known to alter psychostimulant function in brain. Relatively few studies have examined the reinforcing effects of psychostimulants in subjects maintained on high-fat diets. The present experiment compared the rate of acquisition of an operant response for intravenous (i.v.) cocaine infusions (0.2 mg/kg) in rats fed either a chow-pellet diet or a 35.9% (by weight) high-fat diet for 45 days prior to cocaine self-administration testing. Rats maintained on a high-fat diet for 45 days exhibited diminished acquisition of cocaine self-administration, and this effect was not a function of dietary-induced obesity. The results suggest that prolonged exposure to a high-fat diet diminishes the efficacy of cocaine reinforcement.