Prostacyclin (PGI2), an unstable metabolite of arachidonic acid synthesized by vascular endothelial and smooth muscle cells, is a potent vasodilator and endogenous inhibitor of platelet aggregation. Regulation of PGI synthesis by the vessel wall is not well understood. We have investigated the possibility that a product released from platelet granules during degranulation might modify vessel wall PGI2 biosynthesis. We report here that a non-dialysable, platelet-dependent factor in serum dramatically stimulates PGI2 synthesis by cultured bovine aortic endothelium aortic smooth muscle, and adrenal capillary endothelium. Platelet-derived growth factor (PDGF), a releasable peptide contained within platelet alpha granules, stimulates PGI2 synthesis by the above cell types as much as 100-fold. The concentrations of PDGF required to produce these effects are below the level reported in normal human serum. We postulate that in vivo released PDGF may increase vessel wall PGI2 production as part of a negative feedback mechanism controlling platelet aggregation.