Most human B-cell non-Hodgkin's lymphomas arise from germinal centers. Within these sites, the mismatch repair factor MSH6 participates in antibody diversification. Reminiscent of the neoplasms arising in patients with Lynch syndrome III, mice deficient in MSH6 die prematurely of lymphoma. In this study, we characterized the B-cell tumors in MSH6-deficient mice and describe their histological, immunohistochemical, and molecular features, which include moderate microsatellite instability. Based on histological markers and gene expression, the tumor cells seem to be at or beyond the germinal center stage. The simultaneous loss of MSH6 and of activation-induced cytidine deaminase did not appreciably affect the survival of these animals, suggesting that these germinal center-like tumors arose by an activation-induced cytidine deaminase-independent pathway. We conclude that MSH6 protects B cells from neoplastic transformation by preserving genomic stability.