The histologic classification of pulmonary neoplasms can have important implications regarding appropriate management of patients. Although the histologic classification of lung tumors is predominantly based on morphology, ancillary studies such as immunohistochemistry can be used in difficult cases, and the diagnosis of large cell neuroendocrine carcinoma requires confirmation of neuroendocrine differentiation by immunohistochemistry or electron microscopy. We immunostained 142 lung tumors for B72.3, keratin 34betaE12, keratin 7, keratin 14, keratin 17, synaptophysin, and chromogranin to determine the utility of neuroendocrine markers and epithelial markers in the differential diagnosis. Among neuroendocrine carcinomas (small cell carcinoma and large cell neuroendocrine carcinoma), 84% (37 of 44) were chromogranin positive, 64% (21 of 36 small cell, 6 of 6 large cell neuroendocrine) were synaptophysin positive, 5% (2 of 43) were keratin 34betaE12 positive, 9% (4 of 44) were keratin 7 positive, and 5% (2 of 37) of small cell carcinomas and 50% (3 of 6) of large cell neuroendocrine carcinomas were B72.3 positive. Among non-neuroendocrine carcinomas, 5% (5 of 98) were chromogranin positive, 3% (3 of 96) were synaptophysin positive, and 97% (95 of 98) were positive for either keratin 34betaE12 or keratin 7 and 99% (97 of 98) were positive for either keratin 34betaE12, keratin 7 or B72.3. An antibody panel consisting of keratin 7, keratin 34betaE12, chromogranin, and synaptophysin separated 132 of 141 tumors (94%) into distinct groups. We conclude that immunostaining with both neuroendocrine markers and epithelial markers can be useful in the differential diagnosis of lung neoplasms.