Etiological risk factors for proximal (right-sided) colon cancers may be different to those of distal colon and rectal (left-sided) cancers if these tumors develop along distinct pathways. The CpG Island Methylator Phenotype (CIMP+) occurs in approximately 15% of colorectal cancers (CRC) and predominantly in the proximal colon. CIMP+ tumors have frequent methylation of gene promoter regions and increased tissue folate levels. The aim here was to determine whether polymorphisms in 2 genes involved in cellular methyl group metabolism were associated with different risks for right- and left-sided CRC. This population-based case-control study involved 859 incident cases of CRC and 973 sex and age-matched controls. Information on dietary folate and alcohol intake was obtained from food frequency questionnaires and information on the anatomical site of tumors from pathology reports. DNA was collected using FTA cards and genotyping performed for the MTHFR C677T and DeltaDNMT3B C-149T polymorphisms. The MTHFR 677 T allele was associated with increased risk for proximal colon cancer (adjusted odds ratio, AOR = 1.29) but decreased risk for distal cancers (AOR = 0.87). The increased risk for proximal cancers was especially pronounced in older individuals (AOR = 1.49) and those with a low folate diet (AOR = 1.67) or high alcohol consumption (AOR = 1.90). The DeltaDNMT3B-149 TT genotype was protective against proximal colon cancers (AOR = 0.65), but showed no association with the risk of distal colon and rectal cancers (AOR = 1.02). Epidemiological studies on dietary and genetic risk factors for CRC should take into account these may confer different risks for right- and left-sided tumors.