Platelets are an active element in the generation of thrombus and may influence rates of thrombolysis during the administration of plasminogen activators. To assess the potential importance of platelet aggregation in the thrombolytic response to plasminogen activators, we measured rates of thrombolysis induced by tissue plasminogen activator in the presence and absence of a coinfusion of prostaglandin E1 in a rabbit jugular vein model of thrombosis. Rates of lysis were quantified by measuring the half-time for lysis of the thrombus. At all concentrations of tissue plasminogen activator used, prostaglandin E1 markedly reduced the half-time for clot lysis and enhanced somewhat the overall extent of thrombolysis, without affecting significantly either the degree of fibrinogen depletion or the animals' mean arterial pressures. These effects on thrombolytic efficacy were accompanied by ex vivo evidence of platelet inhibition. These data suggest that the antiplatelet prostaglandin E1 may be a very useful adjunctive agent in thrombolytic therapy primarily by virtue of the significant improvement in the rate of thrombolysis that its use affords.