Objective. The goal of the present study was to assess the relationship between the genetic variability in six genes of methyl group (CH(3)) metabolism and the risk of obesity. Methods. Single nucleotide polymorphisms (SNP) were selected among the methylene-tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystationine betha-syntase (CBS), transcobalamin-II (TCN2) and paraoxonase-1 (PON1) genes. The associations between SNPs and the risk of obesity were assessed in a case-control study of obese and normal-weight adolescents (age: 14.9 +/- 1.2 years), and the relationship between SNPs and body fat markers (i.e., body mass index [BMI], percentage body fat [BF%] and waist circumference [WC]) in a cross-sectional study of 1 155 European adolescents (age: 14.8 +/- 1.4 years). Genotyping was performed on an Illumina system and plasma folate level was determined by immunoassay. Results. In the case-control study, there was no evidence for any association between SNPs of MTHFR, MTR, CBS, TCN2 and PON1 and obesity (all p values >= 0.08). In contrast, two SNPs of MTRR were associated with a higher (rs10520873, Odds Ratio: 1.68 [1.18-2.39]; p = 0.004) or lower (rs1801394, 0.61 [0.42-0.87]; p = 0.007) risk of obesity. In the cross-sectional sample, rs1801394 was associated with lower BMI (p = 0.03) and lower waist circumference (p = 0.02). However, after Bonferroni correction these associations were no longer significant. No other significant association or interaction between folate levels and SNPs were detected for anthropometric variables. Conclusion. Our findings do not support an association between MTHFR, MTR, CBS, TCN2 and PON1 SNPs and obesity in adolescence. Further investigations are necessary to confirm the possible association between the rs1801394 variant of MTRR and obesity.