Background: The most common complication of hemodialysis (HD) access graft is thrombosis. Clopidogrel, an inhibitor of platelet aggregation, was assessed to prevent this serious complication. Methods: A prospective study in which 24 patients on chronic HD whose vascular accesses were grafts were divided into two groups: group A (n = 12, 50%) consisted of patients who did not receive antithrombotic therapy after graft creation, and group B (n = 12, 50%) received clopidogrel 75 mg/day from 2 days after surgery onwards. Both groups were not different according to age, gender, cause of renal failure, hematocrit levels, platelet counts and Kt/V. All patients’ thrombotic episodes were followed up from the day of graft surgery until thrombosis was diagnosed. Finally, the patient survival difference between both groups was determined. Results: Eleven thrombotic episodes were diagnosed in group A while one event was reported in group B (p < 0.001). Graft access days of patency were significantly longer in group B compared to group A (380.8 ± 170 vs. 90.1 ± 57.2, p < 0.001). Time that elapsed from dialysis initiation to graft creation was not different (group A 18 ± 12 days, group B 20 ± 10 days). Days on HD were different between both groups (group A 208.9 ± 97.2 vs. group B 583.2 ± 287.0, p < 0.001) and all patients from group A (n = 12, 100%) and 2 patients from group B (16.7%) died (p = 0.001). Major bleeding events were not reported. Conclusions: Clopidogrel significantly decreased thrombotic graft episodes. Patients on clopidogrel had a prolonged vascular access patency, longer time on HD and better survival.