INSM1 is a diagnostic marker for neuroendocrine tumors originating in multiple anatomic sites. In the lung, INSM1 shows 76-97% sensitivity for neuroendocrine tumors overall. Our aim was to characterize INSM1 as a diagnostic marker for small cell carcinoma in the context of its epithelial, lymphoid, and mesenchymal morphologic mimics. Immunohistochemistry was performed on 231 tumors, including lung neuroendocrine tumors, nonneuroendocrine carcinomas of the thoracic cavity, diffuse large B-cell lymphomas, and small round cell sarcomas, using an anti-INSM1 mouse monoclonal antibody. Extent (0-100%) and intensity (1-3+) of nuclear INSM1 staining was multiplied in each case to calculate an H-score. Demographic and clinical information was obtained from the medical record. INSM1 had an overall sensitivity and specificity of 81.5% and 82.7% for small cell carcinoma, respectively, using a threshold established with a receiver operating characteristic curve. 40/48 (82.7%) small cell carcinomas were positive for INSM1, including 19/24 (79%) small cell carcinomas that were negative for chromogranin and synaptophysin. 5/5 carcinoids and 21/28 (75%) large cell neuroendocrine carcinomas showed INSM1 expression. Among nonneuroendocrine tumors, 7/38 (18%) lung adenocarcinomas, 2/17 (12%) lung squamous cell carcinomas, 4/10 (40%) thymic carcinomas, 4/12 (33%) adenoid cystic carcinomas, 1/19 (5%) diffuse large B-cell lymphomas, 4/11 (36%) alveolar rhabdomyosarcomas, and 4/23 (17%) Ewing sarcomas were positive for INSM1. No synovial sarcomas or desmoplastic small round cell tumors were positive. Weak, focal INSM1 expression alone is insufficient as a diagnostic marker for small cell carcinoma, but is sensitive and specific, easy to interpret in small biopsies, and makes a valuable addition to a diagnostic panel.