To determine if alterations in endothelial prostaglandin production occur after long-term cocaine use, 26 New Zealand White rabbits were randomized to a low fat diet with (n = 12) or without (n = 14) daily intravenous cocaine (2 mg/kg body weight). Rabbits were killed at 6 or 12 weeks. Segments of aorta were examined in blinded manner for histologic changes. Additional slices were incubated in oxygenated Krebs buffer and release of 6-keto-prostaglandin F1 alpha, thromboxane B2 and prostaglandin E2 was assayed by radioimmunoassay. Minimal intimal histologic changes were seen in the aorta of three cocaine-treated rabbits. At 12 weeks 6-keto-prostaglandin F1 alpha was increased in the cocaine group (p = 0.063) as compared with levels in the control group. When rabbits killed at 6 and 12 weeks were considered together, increases in thromboxane B2 (p = 0.044) and a trend to increased prostaglandin E2 (p = 0.083) were seen in the cocaine group. The ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha was increased in the cocaine group compared with that in the control group (p less than 0.02). These data suggest that an increase in prostaglandin production occurs in the vascular endothelium of rabbits ingesting cocaine before gross histologic changes are evident. In addition, thromboxane B2 increases disproportionately with respect to 6-keto-prostaglandin F1 alpha, suggesting that a milieu for thrombosis may exist in users of cocaine.