Vascular prostacyclin (PGI2) regulates platelet function and blood flow. In systemic sclerosis (SS) there is increased platelet aggregation (PA) but no information is available on the platelet/PGI2 relationship. We evaluated platelet sensitivity to a PGI2 analogue ZK36374 in 17 SS patients and 18 controls. The percentage (%) inhibition of PA was measured at two doses of ZK36374 with saline giving the 100% baseline. In the SS group 2 ng ZK36374 produced a percentage inhibition of 19 + 14 compared to a control value of 60 + 21, and 3 ng a percentage inhibition of 47 + 21 in the SS group and 82 + 20 in the controls. In 11 SS patients treated with either prostaglandin E or nifedipine the sensitivity approached normal. These data suggest that SS platelets are less sensitive to the inhibitory effect of PGI2 on PA. This may contribute to the vascular lesions of SS. Other cells are resistant to the effects of PGI2 and our findings support this picture of cellular resistance.