Polymorphisms in the genes coding folate-metabolizing enzymes affect the risk of some forms of cancer. We investigated the association between these polymorphisms and non-Hodgkin lymphoma (NHL) risk in a population-based study (583 cases and 1700 controls). The MTHFR 677TT and CT genotypes were associated with reduced risk for NHL [odds ratios (OR) = 0.79; 95% confidence intervals (CI) = 0.65-0.98 for 677CT and 0.61; 0.45-0.82 for 677TT] and diffuse large B-cell lymphoma (DLBCL) (OR = 0.68; 0.51-0.88 for 677CT; OR = 0.56; 0.38-0.83 for 677TT). The MTHFR 1298CC genotype was associated with increased risk for NHL (OR = 1.71; 1.07-2.75) and T-cell lymphoma (OR = 3.05; 1.53-6.11). The MTRR 66GG genotype was associated with increased risk for DLBCL (OR = 1.56; 1.03-2.38) and the TYMS 2R2R genotype was associated with increased risk for T-cell lymphoma (OR = 2.83; 1.33-6.01). Using subjects with 3RG3RG as a reference group, TYMS 2R2R was associated with increased risk for T-cell lymphoma (OR = 2.46; 1.04-5.79). Interestingly, we observed a reduced association between the TYMS 2R3RG genotype and DLBCL (OR = 0.61; 0.38-0.99). These results suggest that MTHFR, MTRR and TYMS polymorphisms may play a significant role in the risk for NHL.