In patients with thrombophilia caused by reduced physiological anticoagulation, renal transplant failure occurs more frequently. Previous studies showed the importance of the protein C system, a physiological anticoagulatory pathway that inhibits thrombus formation. However, excess activation of the hemostatic system also may result in thrombosis. The G20210A mutation in the prothrombin gene is such a prothrombotic risk factor that results in increased thrombus formation because of elevated factor II levels in plasma. We analyzed graft function in 270 consecutive patients who received 311 renal transplants. The presence of a normal or mutated prothrombin allele was determined by polymerase chain reaction amplification and restriction fragment length polymorphism analysis of genomic DNA. Demographic data were extracted from hospital records. Graft survival was calculated for patients with and without the G20210A mutation. We identified 9 patients heterozygous for the G20210A mutation in the prothrombin gene who had received a total of 12 renal transplants. Of these 12 transplants, 2 grafts were lost within the first year. Median graft survival for patients heterozygous for the 20210A allele was 65.9 months (range, 0 to 101 months) compared with 149 months (range, 0 to 237 months) for patients homozygous for the normal 20210 G allele (P = 0.02). The G20210A mutation represented a 2.95-fold (95% confidence interval, 1.03 to 8.46) increase in risk for graft loss. Only 1 patient with this mutation achieved graft function exceeding 101 months. The G20210A mutation of the prothrombin gene is an independent risk factor for graft failure.