Abstract： Objective To investigate the role of hMSH2 in the pathogenesis of sporadic insulinomas and to determine whether the expression of hMSH2 could be used to differentiate benign sporadic insulinomas from malignant ones. Methods Fifty-five sporadic insulinomas (40 benign and 15 malignant tumors) resected from 50 patients were obtained. Expression of hMSH2 was detected by immunohistochemistry staining. DNA was obtained from micradissected tissue. Loss of heterozygnsity (LOH) of hMSH2 gene was detected by PCR-LOH. 6 microsatellite markers were selected on 3 chromosomes, and microsatellite instability (MSI) status of tumor tissue were detected by PCR. The findings were analyzed in relation to the clinicopathological characteristics. Results Down-regulation of hMSH2 expression was found in 13% of 55 sporadic insulinomas. LOH of the hMSH2 gene was not present in 55 insulinomas. High frequency MSI (MSI-H, MSI occurred in at least 2 out of 6 sites) was present in 36% (20/55) of all the insulinomas. Down-regulation of hMSH2 expression was found in 33% of the 15 malignant tumors, while it was 5% in benign tumors (P < 0. 05). Conclusions Down-regulation of mismatch repair gene hMSH2 may be correlated with the degree of tumor malignancy. The expression of hMSH2 could be used as a potential marker for distinguishing benign insulinoma from malignant ones.