We report a case of colonic adenosquamous carcinoma with MSI-H (microsatellite instability–high) in a 43-year-old male who presented with bowel obstruction due to a circumferential mass involving the descending colon and splenic flexure. Microscopically, it showed poorly differentiated adenocarcinoma with squamous differentiation, tumor infiltrating lymphocytes >3/high-power field, and mild peritumoral lymphocytic response. Immunohistochemistry was equivocal for MLH-1, PMS-2, and MSH-2, with retention of MSH-6 expression. Polymerase chain reaction testing demonstrated MSI-H pattern with instability of BAT-25, BAT-26, and NR-21. Review of the literature revealed only one recently published case of MSI-H adenosquamous carcinoma. The role of MSI in adenosquamous carcinoma pathogenesis is still unknown. In conclusion, MSI testing in colonic adenosquamous carcinoma combined with other MSI-related clinical and histological features is indicated.