Objective: To investigate the clinicopathological features of colon squamous cell carcinoma and adenosquamous carcinoma. Methods: The clinicopathological data and prognosis of 4 patients with colonic squamous cell carcinoma or adenosquamous carcinoma were collected retrospectively. Results: There were 1 male and 3 female, and the age ranged from 29 to 76 years old. Serum CA19-9 was increased in 2 cases, which were 88.25 ng/mL and 553.13 ng/mL, respectively. Serum CEA increased in 2 cases, which were 116.39 U/mL and 37.22 U/mL, respectively. Three cases occurred in ascending colon and 1 case in descending colon. Microscopically, the squamous cell carcinoma of 4 cases was arranged into irregular nesting or flake shape, the tumor cells were polygonal or irregular, the cells were eosinophilic and expressed P40 and P63, while the adenocarcinoma of 2 adenosquamous carcinoma cases was arranged into irregular glandular tubules or cribriform, and the cell nucleus was deeply stained and expressed CAM5.2 and CK20. P16 was expressed in 3 cases. One case was complicated with schistosome. No patient was with human papilloma virus infection. Mismatch repair protein absently expressed in 3 cases. Three cases were complicated with KRAS gene mutation. At the last of follow-up, 1 patient died at 16.4 months after surgery, and the remaining 3 patients survived without recurrence (median follow-up time: 42 months). Conclusions: Squamous cell carcinoma and adenosquamous carcinoma are rare histopathological types of colorectal cancer with poor biological behavior, often accompanied by loss of mismatch repair protein expression and KRAS gene mutation. Radical resection is an effective way to obtain a good prognosis.