The hMSH2 gene, a member of the mismatch repair (MMR) pathway, plays a key role in the maintenance of genomic integrity. The common sequence variation in hMSH2, IVS12-6 T>C, has been implicated in cancer risk. However, the results of published studies on this polymorphism remain conflicting. Hence, we conducted a meta-analysis to clarify the role of the hMSH2 IVS12-6 T>C polymorphism in cancer. We performed a comprehensive literature search updated to March 2011 of studies on the associations between the hMSH2 IVS12-6 T>C polymorphism and cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. Thirteen studies involving 7,527 patients and 8,762 control subjects were included in this meta-analysis. The overall results indicated no major influence of the polymorphism on cancer risk. However, stratified analysis by cancer types showed that the hMSH2 IVS12-6 polymorphism increased the risk for non-Hodgkin's lymphomas (heterozygote comparison: OR=1.62; 95% CI 1.06-2.47). When stratified by the source of controls, significant associations were observed in hospital-based populations (heterozygote comparison: OR=1.28; 95% CI 1.02-1.61). These results indicate that the polymorphism of hMSH2, IVS12-6, may cause a different effect in different types of cancers. To draw more comprehensive conclusions, further prospective studies with larger numbers of participants worldwide are required to examine the associations between this polymorphism and cancer risk.