Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). Among 609 CRC cases and 1,663 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852), we estimated CRC risk according to methyl donor intake across genotypes of folate metabolizing enzymes and methyltransferases.Although diet-gene interactions were not statistically significant, methionine intake was inversely associated with CRC among subjects having both common rs2424913 and rs406193 DNMT3B C > T genotypes (highest versus lowest tertile: RR = 0.44; p (trend) = 0.05). Likewise, vitamin B2 was modestly inversely associated among individuals with the MTHFR c.665CC (rs1801133) genotype (RR = 0.66; p (trend) = 0.08), but with a significant reduced risk when </= 1 rare allele occurred in the combination of folate metabolizing enzymes MTHFR, MTRR and MTR (RR = 0.30; p (trend) = 0.005). Folate or vitamin B6 were neither inversely associated with CRC nor was methyl donor intake associated with the CpG island methylator phenotype (CIMP).Despite the absence of heterogeneity across genotypes, might an effect of methyl donors on CRC be more pronounced among individuals carrying common variants of folate metabolizing enzymes or DNA methyltransferases. Combining genotypes may assist to reveal diet associations with CRC, possibly because rare variants of related genes may collectively affect specific metabolic pathways or enzymatic functions.