X-linked hyper-immunoglobulin M syndrome (XHIGM) is a primary immunodeficiency disorder characterized by severe defects of both cellular and humoral immunity due to impaired expression of CD40 ligand on activated T lymphocytes. Patients with XHIGM usually present with a wide variety of infections caused by common and opportunistic pathogens including Pneumocystis jirovecii. In addition, subjects with XHIGM have an increased risk for hepatocellular and bile duct carcinomas, which are rarely observed in other primary immunodeficiencies. We present here clinical, immunological, and molecular findings of four patients with CD40 ligand deficiency associated with neuroendocrine carcinoma (NEC). NEC developed as a rapidly disseminated solid cancer leading to death in three patients. Data presented here and published previously suggest that CD40 ligand deficiency may predispose patients for the development of NEC. Histochemical findings suggested that CD56, in addition to cytokeratin and chromogranin A, may be a useful marker for early detection of NEC. We conclude that patients with XHIGM should be carefully followed to diagnose and treat NEC, a formidable neuroendocrine cancer.