Hyperhomocysteine has been reported to be an important risk factor for the development of atherosclerosis. Identification of risk factors, such as hyperhomocysteinemia, is crucial for a better understanding of the events that lead to degenerative processes in the vascular system and for a correct understanding of the potential role of methylene-tetrahydrofolate reductase enzymes (MTHFR) to help in the treatment of vascular disease observed in chronic allograft nephropathy (CAN). In this study we analyzed the plasma homocysteine concentrations and MTHFR C677T and A1298C polymorphism frequencies among 110 renal transplant recipients (53 with CAN and 57 with normal renal function). All recipients had undergone renal transplantation at least 12 months prior to this investigation to establish a possible correlation with the posttransplant outcome. Plasma homocysteine concentrations were measured by liquid chromatography-tandem mass spectrometry and MTHFR polymorphisms were investigated by the PCR-RFLP technique. The results demonstrated that in renal transplant recipients, hyperhomocysteinemia in addition to the presence of the allelic variants for both MTHFR polymorphisms (677T/1298C) might play a role as an additional risk factor for CAN. We understand that analysis of these polymorphisms might have a role in the CAN process. Therefore, studies to evaluate their presence in renal transplant patients may be extremely useful to individualize immunosuppressive protocols to inhibit or retard the progression of CAN.