Reports on the effect of recombinant human erythropoietin (r-HUEPO) on the platelet activity are conflicting. In the present study platelet function and coagulation factors were investigated in 20 patients with end-stage renal failure on maintenance hemodialysis. The patients were randomized into two groups and, in a crossover design, investigated during intravenous and subcutaneous administration of rHUEPO. The two groups started with a different administration form (intravenously in group 1 and subcutaneously in group 2), and each mode of treatment was given for 3 months. At entrance into the study the platelets were hyperaggregable to exogenous stimulation with collagen (COL) in both groups. Group 1 developed increasing platelet sensitivity to adenosine diphosphate (ADP; 0.01 < p < 0.025) during intravenous treatment. Concomitantly, three episodes of arteriovenous fistula thrombosis occurred. In group 2 one event of fistula thrombosis occurred despite there being no change in platelet reactivity to ADP. After 3 months on r-HUEPO, the platelet reactivity to ADP decreased significantly in both groups, but also the reactivity to COL declined significantly: 0.01 < p < 0.025 (group 1) versus 0.001 < p < 0.005 (group 2). The platelet reactivity to ristocetin remained unchanged in group 1 but decreased significantly in group 2. In group 1 fibrinogen was increased significantly (0.001 < p < 0.005) at the time of the clotting events. The factor VIIL·coagulant activity increased, but antithrombin III, activated factors X and XIII, activated protein C, activated thromboplastin time, and partial prothrombin time remained unchanged. Furthermore, 4 patients in group 1 and 2 patients in group 2 required an increased dose of heparin after 2-3 months of investigation. Thus, r-HUEPO seemed to influence platelet function. Enhanced activity was observed during intravenous administration. Eventually, platelet reactivity to ex vivo stimulation decreased in both groups. Thus, intravascular hemostatic activation seemed to occur following r-HUEPO administration. An increase in hematocrit is probably of importance, but according to the present data, transient platelet activation may also be a contributory factor.