Platelet activating effect of cigarette smoking appears to be important in the development of atherosclerosis. We previously demonstrated a reduced sensitivity of platelets to exogenous prostacyclin (PGI2) in vitro from patients with proven atherosclerotic disease, indicating a possible role of altered platelet function in the development of atherosclerosis. We now hypothesize that cigarette smoking might be an important cause of altered platelet sensitivity to PGI2 observed in patients with atherosclerosis. To test this hypothesis, the response of platelets to exogenous PGI2 was tested in chronic smokers and non-smokers, prior to and after smoking two cigarettes (active smoking) and prior to and after exposure to a tobacco smoke-contaminated atmosphere (passive smoking). This study indicates that platelets of chronic smokers are less sensitive to exogenous PGI2 than platelets of non-smokers. In addition, active as well as passive smoking decreases platelet sensitivity to PGI2 in non-smokers, whereas chronic smokers exhibit no further decline. We conclude that decreased platelet sensitivity to PGI2 might be an important contributing factor to the altered platelet function observed in patients with atherosclerosis.