Genetic determinants for high homocysteine (Hcy) levels are now well known. We studied several single nucleotide polymorphisms (SNP) in Hcy-regulating genes [methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C; methionine synthase (MS) A2756G; methionine synthase reductase (MTRR) A66G] in relation to total plasma Hcy levels, transplant coronary artery disease and thromboembolic episodes in 84 heart transplant patients, and we compared the incidence of these polymorphisms with those in a healthy adult controls. At least one copy of the G allele of the MTRR A66G SNP was found in a significantly greater proportion of cardiac transplant (CTX) recipients compared with controls (94.0% vs. 79.9% respectively). None of the SNP analyzed were correlated with total Hcy plasma levels or the presence of transplant coronary artery disease. However, MS A2756G was significantly associated with cobalamin levels (AA genotype: 290 +/- 122 pmol/l; AG: 381 +/- 151 pmol/l and GG: 415 +/- 100 pmol/l), as was MTRR A66G (AA: 478 +/- 219 pmol/l, AG: 306 +/- 124 pmol/l and GG: 306 +/- 123 pmol/l). MTRR A66G was also correlated with serum folate. No association was found with thromboembolic events. In conclusion, there was a significant difference in the frequency of the G allele genotype of the MTRR A66G in CTX patients versus controls. Differences in cobalamin and folate levels with the MTRR A66G and MS A2756G polymorphisms were noted. Thus, SNP in Hcy-regulating genes may be important determinants of vitamin metabolism in CTX, raising the question of increased vitamin requirements to minimize increased plasma Hcy in this high-risk group.