Single nucleotide polymorphisms (SNPs) identified in mismatch repair (MMR) genes hMLH1 and hMSH2 may have a functional role, thus influencing susceptibility to CRC, and this susceptibility may vary according to population. This case-control study examined allele frequencies of two SNPs, the common hMLH1 I219V and the rare hMSH2 G322D, in two genetically distinct Canadian populations: the heterogeneous population from Ontario and the founder population of Newfoundland. Individually, each SNP did not increase susceptibility to CRC and their frequencies did not vary between the two provinces. In Ontario CRC cases, G322D was associated with family history when compared with low risk cases (p=0.02), while in Newfoundland cases, 1219V was associated with family history based on age and cancer-modified Amsterdam criteria (p=0.04). The I219V variant also exhibited a protective effect in late stage tumours among Ontario cases (p=0.03). G322D and I219V were not associated with other clinicopathological features such as age at onset, MSI status, tumour site and tumour grade. These findings indicate that MMR low penetrance alleles may indeed contribute to CRC risk and progression.