Nasopharyngeal carcinoma (NPC) occurred in five members in three generations of a white American family of Scandinavian descent. Six other family members had malignancies including malignant melanoma, malignant lymphoma, squamous cell carcinoma of the tongue, adenocarcinoma of the colon, and asynchronous bilateral in situ and invasive ductal carcinomas of the breast. There was also a history of autoimmune disorders and exposure to smoke, fumes, and chemicals in some family members. Regression analysis revealed a significant covariate risk for exposure to smoking, alcohol ingestion, dust, salted or spicy foods, and poorly ventilated conditions. According to segregation analysis, the susceptibility to nasopharyngeal carcinoma and other malignancies in this family was transmitted as an autosomal codominant characteristic. A specific histocompatibility antigen (HLA) haplotype of Al-B37-DR6 was associated with a predisposition for NPC, but no linkage was identified. Laboratory studies in selected family members did not reveal significantly elevated levels of Epstein-Barr virus antibodies or serum carcinoembryonic antigen. No specific karyotypic abnormalities were identified with peripheral blood chromosome analysis. This family was an example of apparent autosomal codominant susceptibility to NPC and other malignancies. The relationship of malignancy to the HLA haplotype of Al-B37-DR6, autoimmune disorders, and cytogenetic abnormalities was intriguing but not defined clearly.