Rationale: Cronkhite-Canada Syndrome (CCS) is an idiopathic, nonhereditary syndrome haracterized by gastrointestinal (GI) polyposis and ectodermal changes including alopecia, onychatrophia, and pigmentation. CCS colon polyps were previously considered to be benign neoplasms. However, serrated adenoma was reported to be associated with malignant neoplasms in some cases of gastric and colorectal carcinomas, and esophageal cancers. Although malignant colon and gastric cancer have been reported in CCS, reports of distant metastasis have been rare in CCS. Patient concerns: A 58-year-old male was referred from a nearby hospital with diarrhea and weight loss. The patient was hypoproteinemia (17.9g/L), and multiple polyps were observed in the large intestine. Healsohad alopecia, onychatrophia, and dysgeusia. Diagnoses: The presence of multiple polyps and associated symptoms of alopecia, onychatrophia, pigmentation, and dysgeusia informed the diagnosis of CCS. Interventions: He was treated with 20 mg dexamethasone acetate per day for about 3 months, 10mg for about 9 month, 5mg for about 1 year, and then maintained on 5mg daily. Three years after starting treatment, colonoscopy revealed colon cancer and colon adenomas. A sigmoidectomy revealed 4 well-differentiated adenocarcinomas of the ulcerating type in the sigmoid colon, and tubularadenomas throughout the rest of the large intestine. He was treated with FOLFOX6 for 6months. At this stage liver metastasis was found. A right hepatectomy was performed confirming hepatic metastasis of colonic adenocarcinoma, which was GPC-3(-), CD34(-), CK20(+), CDX-2(+), Hep(-), CK19(+), and CK8(+). The patient received 3 courses of hepatic arterial infusion chemotherapy. Outcomes: The patient's status has been stable for more than 2 years, and there was no tumor recurrence or metastasis occurred. Lessons: CCS is a rare cause of multiple polyposis most often treated with hormone therapy. Regular follow-ups are very important to ensure discovery of malignant tumors at an early stage. Studies with longer-term observations and larger sample sizes will be required to confirm these observations. However, characterization of molecular markers for the early detection of malignant transformation that might allow less invasive and more cost-effective surveillance of colon cancer is urgently sought.