Histopathologic classification of lung carcinoma is important, as a prognostic factor and in the evaluation of treatment modalities. Although the World Health Organization classification of lung cancer is based on routine microscopy, immunohistochemistry is an important additional aspect in modern pathologic practice. This study examines whether the main histologic types of lung carcinomas are more reliably diagnosed with immunohistochemical technique using antibodies for the lung tissue-specific antigen thyroid transcription factor-1 (TTF-1) and a panel of cytokeratin (CK) antibodies. Forty-five cases of lung cancer (12 squamous cell carcinoma, 13 small cell carcinoma, 11 adenocarcinoma, 9 large cell carcinoma [LCC]/pleomorphic carcinoma) were stained with antibodies to CK CAM5.2, CK5, CK7, CK20, and TTF-1. All 45 cases were positive with CAM5.2, 16 of 45 cases with CK5, 34 of 45 cases with CK7, 4 of 45 cases with CK20, and 29 of 45 with TTF-1. Squamous cell carcinoma (epidermoid carcinoma) had the immunophenotype CK5+/TTF-1-, and at least 20% were also positive with CK7. Most nonepidermoid tumors had the "lung-specific" phenotype CK5-/TTF-1+; all small cell carcinomas had the phenotype CK5-/CK8+/TTF-1+, all adenocarcinomas CK5-/CK7+/TTF-1+ and (more than 50%) of LCC CK5-/CK7+/TTF-1+. Thus, more than 50% of LCCs were of the same phenotype as adenocarcinomas. The immunophenotypes of the main histologic types of lung carcinoma are stable and highly reproducible. However, because of considerable overlapping, immunophenotyping should not be used alone for histopathologic classification of lung cancer, but only as an adjunct to light microscopy. It is also suggested that CK5+ lung carcinomas with basaloid features should be regarded as variants of squamous cell carcinoma and not as LCC.