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Long-term survival of renal transplant recipients seems to be influenced by the occurrence of thromboembolic complications and cardiovascular disease. Preliminary data available in the literature found high levels of cysteine (Cy) as a risk factor for deep venous thrombosis independently of high homocysteine (tHcy) levels, but no data are available about Cy levels in renal transplant recipients.To investigate Cy, tHcy, and plasminogen activator inhibitor-1 (PAI-1) levels and the prevalence of 5,10-methylenetetrahydrofolate reductase (MTHFR) in renal transplantation, we studied 70 stable renal transplant recipients and 66 age- and sex-matched normal subjects as controls.Cy, tHcy, and PAI-1 levels were significantly higher in renal transplant recipients with respect to controls (Cy: 254 μmol/L [117–466] vs. 198 μmol/L [99–331], P <0.001; tHcy: 17.0 μmol/L [4.0–68] vs. 8.1 μmol/L [2.0–24.0], P <0.00001; PAI-1: 16.8 IU/ml [5.1–45.5] vs. 7.9 IU/ml [4.0–18.0], P <0.00001). High Cy levels were detected in 35.8% of patients. Hyperhomocysteinemia, both in the fasting state and postmethionine loading test, was diagnosed in 90% of cases. The odds ratios for Cy and tHcy levels within the fourth quartile with respect to the other quartiles were markedly increased in renal transplant recipients even after adjustment for prevalent cardiovascular risk factors, glomerular filtration rate, tHcy and, Cy, respectively (Cy: 29.0 μmol/L [95% CI 7.0–111]; tHcy: 29.9 μmol/L [95% CI 7.5–118.1]). Fasting tHcy levels correlated well with PAI-1 (r =0.65;P <0.0001) but not with Cy levels (r =0.10;P =0.4). The prevalence of the MTHFR 677TT genotype in renal transplant recipients was not significantly higher in patients than in controls (mutant allele frequency: 0.48 in patients and 0.47 in controls) and was associated with significantly higher fasting and postmethionine tHcy levels both in controls and patients. After 2 months of vitamin supplementation, tHcy (Pre: 17.0 μmol/L [4.0–68]; Post: 7.5 μmol/L [2.3–21.9];P <0.0001) and PAI-1 levels (Pre: 16.8 IU/ml [5.1–45.5]; Post: 10 IU/ml [2.0–25];P <0.001) were significantly decreased, whereas Cy levels showed a small decrease that did not reach statistical significance (Pre: 254 μmol/L [117–466]; Post: 209 μmol/L [168–300];P =0.3). Patients with the MTHFR 677TT genotype had the major percentage of decrease of tHcy levels with respect to the other genotypes.In conclusion, this study demonstrates the presence of elevated Cy plasma levels in renal transplant recipients. Vitamin supplementation reduces tHcy but not Cy levels, and the amount of decrease seems to be influenced by the MTHFR genotype.