Dazoxiben, a thromboxane synthase inhibitor, inhibits arachidonic acid induced aggregation in platelet-rich plasma from some donors only ("responders"). We have studied the effect of dazoxiben in vitro on platelet aggregation and prostaglandin (PG) metabolism and the influence of the incubation period and of exogenously added serum albumin (SA). SA, which increases the production of anti-aggregatory PGD2 from cyclic endoperoxides, induced "non-responder" human platelets to respond. With rabbit platelets, however, that are insensitive to PGD2, exogenous SA failed to potentiate dazoxiben-induced inhibition. The ratio between PGD2 and TXB2 + PGE2 formed was crucial in determining the response of human platelets to dazoxiben: whenever this ratio was high, platelet aggregation was inhibited. SQ 22536, an adenylate cyclase inhibitor, and NO164, a PGD2 antagonist, reversed the inhibition by dazoxiben in human platelet-rich plasma, stressing the importance of a PGD2 mediated rise of cyclic AMP for the effectiveness of a thromboxane synthase inhibitor.