The occurrence of multiple primary malignancies (MPM) in one patient is a rare but increasingly frequent event, partly due to medical advances in diagnosis and therapy. A number of theories have been proposed to explain MPM, but none have been proven. A key risk factor appears to be family history. We present the case of a 43-year-old male with multiple cancers who was first admitted to the hospital for an undifferentiated pleomorphic sarcoma/pleomorphic malignant fibrous histiocytoma (pG2T2bN0Mx stage III) of the right scapula in May 2009. The patient underwent three tumor resections in situ due to tumor recurrence. During the period of chemotherapy and radiotherapy, computed tomography (CT) revealed a 10x10-cm enhancing soft mass of the ascending colon, which was diagnosed as mucinous adenocarcinoma in a pathological report. Laboratory data showed elevated serum levels of carcinoembryonic antigen (CEA, 20.0 μg/l; normal range, 0.0-10.0 μg/l). Certain family members of the patient had been diagnosed with endometrial, colon and pancreatic cancer. None of the family had a smoking history or presented with familial adenomatous polyposis (FAP). The patient with hereditary non-polyposis colorectal cancer (HNPCC), whose family fulfilled Amsterdam Criteria I (AC I), has remained free of disease for 15 months. Family history may be a key risk factor for MPM and HNPCC, the detailed molecular mechanisms of which remain to be elucidated. This case report with an investigation of family history may improve the clinical recognition of HNPCC and MPM.