Heparin-resistant blood clotting in hemodialysis, caused mainly by platelets activated with artificial materials, was ameliorated by oral administration of a newly developed anti-platelet agent, 4-cyano-5,5-bis (4-methoxy phenyl)-4-pentenoic acid (E5510, Eisai Co. Ltd., Tokyo, Japan). Six hemodialysis patients, who were given 0.5. 1, 2, and 4 mg of E5510 orally 1 to 2 hr before starting hemodialysis, underwent hemodialysis using a hollow fiber dialyzer (PMMA or cellulose acetate). The platelet aggregation rate was depressed according to dose response, and fell to less than 30% of the initial value with 2 mg of E5510. Plasma thromboxane B2 concentration was depressed significantly. Bleeding time was mildly but not significantly prolonged. Based on these results, we tried heparin-free hemodialysis using E5510 as sole anticoagulant. Six of nine patients were successfully hemodialyzed with minimal blood clotting in the dialyzer and drip chambers. Three patients needed additional low dose heparin to prevent blood clotting in the circuit's air trap. Neither hemorrhagic complications nor other side effects were observed in these cases. E5510 is considered to be a promising oral anti-thrombogenic agent for patients with heparin-resistant blood clotting or heparin-free hemodialysis.