Moderate hyperhomocysteinemia has been identified as a new independent risk factor for cardiovascular and neurodegenerative diseases. This fact has produced interest in the study of genetic variants involved in homocysteine metabolism and its relationship to pathogenesis. Recently, more than 15 different genes were studied for their relationship to plasma homocysteine levels. We determined the influence of genetic variants in five genes (5,10-methylenetetrahydrofolate reductase (MTHFR) 677C --> T, serine hydroxymethyltransferase (SHMT) 1420C --> T, thymidylate synthase (TS) 2R --> 3R, catechol-O-methyltransferase (COMT) 1947G --> A and transcobalamin (TC) 776C --> G) on plasma homocysteine, folic acid and parameters of vitamin B12 metabolism in 111 vegetarians (mean age: 46 +/- 15 years) and 118 healthy seniors (mean age: 82 +/- 6.5 years). Median homocysteine concentration in plasma was significantly influenced by the MTHFR genotypes in both populations. In the vegetarians the median homocysteine level was increased by 8 micromol/l in individuals homozygous for the mutation as compared to wild-type or heterozygous genotypes (20.4 micromol/l vs. 12.9 and 12.7 micromol/l, respectively). This unexpected increase was observed although the folate levels were in medium to elevated ranges. Our results suggest that vegetarians have a higher demand for folate to neutralize the genotype effect. Preclinical vitamin B12 deficiency in vegetarians may be the cause for disturbed remethylation and folate trap. Plasma homocysteine was not significantly influenced by the SHMT, TS, COMT and TC mutations. In addition, for the TC mutation a trend toward cellular vitamin B12 deficiency was observed. The methylmalonic acid (MMA) levels were slightly elevated and the holotranscobalamin-II (holoTC-II) levels decreased. In the vegetarian group a significant relationship between the COMT genotype and holoTC-II concentration in plasma was determined, whereas the high activity COMT genotype (G/G) resulted in increased levels (35 micromol/l vs. 21 micromol/l for heterozygous and low activity genotypes). The MMA levels were inversely correlated to holoTC-II concentrations. In conclusion, the study on vegetarians and seniors documents interesting lifestyle-genotype interactions. Although the TC and COMT mutations influence cellular vitamin B12 metabolism, this effect did not result in overt homocysteine elevation.