We report a case of a 53-year-old woman who presented with rectal bleeding and a 9.5 cm hemicircumferential ascending colon mass. Histology revealed adenosquamous carcinoma (ASC), a rare subtype comprised of malignant squamous and glandular elements. Immunohistochemistry revealed loss of MLH1/PMS2 expression and retained MSH2/MSH6 expression in squamous and glandular components, indicative of microsatellite instability (MSI). MSI is caused by loss-of-function defects in DNA mismatch repair genes, leading to increased susceptibility to a variety of neoplasms; the role of MSI in colorectal ASC is unknown. The tumor was negative for MLH1 gene promoter hypermethylation, the patient had a germline MLH1 mutation, and met criteria for Lynch syndrome. To our knowledge this is the first report of a MSI-high colorectal carcinoma (CRC) showing adenosquamous histology. Further evaluation of MSI status in colorectal ASC may be warranted as this may be another histologic type of CRC associated with MSI.