To study the significance of cytologic features in distinguishing small cell carcinoma (SCC) from non-small cell carcinoma (NSCC). Prospective study of 76 patients with lung carcinoma. Percutaneous fine needle aspiration and bronchial washings stained with Papanicolaou and May-Grünwald-Giemsa stain were used for categorization of tumors according to the World Health Organization classification. Each tumor was also scored for the presence or absence of standard cytologic criteria used in the diagnosis of SCC. Data were analyzed for sensitivity, specificity and significance using the chi 2 and Fisher exact tests. Undifferentiated and unclassified tumors were examined immunocytochemically for the presence of neuron-specific enolase, epithelial membrane antigen and leukocyte common antigen. Cytologic diagnoses were compared with histopathologic diagnoses. Seventy-six lesions classified on cytomorphology consisted of SCC (15), NSCC (50), non-Hodgkin's lymphoma (1), carcinoid (1) and undifferentiated or poorly differentiated carcinomas (9), 2 of which showed nuclear molding and salt-and-pepper chromatin. Immunocytochemistry and biopsy confirmed the diagnosis of SCC in those two patients. Nuclear molding, cell size and scant, basophilic cytoplasm were highly sensitive and specific by univariate analysis for distinguishing SCC from NSCC. Other features, such as salt-and-pepper chromatin, crush artifact and apoptotic bodies, also had significantly high specificity; however, their low sensitivity precluded their usefulness in separating SCC from NSCC. Thus, morphologic evaluation plays a major role, while immunocytochemistry can make a limited contribution in differentiating SCC from NSCC.