Preincubation of rabbit platelet-rich plasma with cocaine hydrochloride, at low and high concentrations, increased the platelet responsiveness to arachidonic acid, in terms of the aggregating response and the thromboxane production. The thromboxane levels released by collagen-stimulated platelets were increased after incubation with low concentrations of cocaine, while marked decreases were observed after incubation with high doses of cocaine. No effects on platelet aggregation induced by collagen and ADP were observed when low concentrations of cocaine were added; on the other hand, high doses of the anaesthetic were found to block the aggregating effects of these two agents. Specific studies showed cocaine to have an inhibitory activity on prostacyclin release when the aortic tissue was mechanically and thermically stimulated. By contrast, the prostacyclin synthesis by 'exhausted' aortic rings incubated with arachidonic acid appeared to be enhanced after addition of cocaine. These results lead us to believe that cocaine modifies both the Ca++ membrane binding and the extent of Ca++ influx, thereby increasing the permeability to arachidonic acid and altering the affinity of the membrane binding sites for the aggregating agents.