Patients with small-cell lung carcinoma (SCLC) rarely present with pleural effusions. Based on morphology alone, recognition of SCLC in effusion cytology may be challenging because of the resemblance of neoplastic cells to lymphocytes. Immunocytochemistry may be helpful in its diagnosis. The objective of this study was to review the morphology and evaluate the use of immunocytochemistry in diagnosing SCLC in pleural fluids. Patients with SCLC who presented with pleural effusions were identified during a 6-yr period. The cytology and medical records were reviewed. Formalin-fixed, paraffin-embedded cell blocks of fluid specimens were immunostained with neuroendocrine markers (chromogranin A and synatophysin), cytokeratin 20 (CK20), and thyroid transcription factor-1 (TTF-1). The latter is a nuclear transcription protein that is expressed in normal respiratory epithelium and also in more than 90% of SCLCs. Of the 256 patients diagnosed with SCLC during the study period, 8 (2.7%) patients (3 females and 4 males, age range from 56-85 yr) also developed pleural effusions. One patient had 2 fluid specimens during the course of their disease, giving a total of 9 specimens. Four specimens had a positive cytologic diagnosis of SCLC, and 2 were initially diagnosed as suspicious for SCLC. The remaining 3 specimens were negative for SCLS. The specimens with a positive or suspicious diagnosis showed single and aggregates of small to medium-sized single cells with a high nuclear: cytoplasmic (N: C) ratio, round to angulated nuclei, and salt-and-pepper chromatin. Nuclear molding was also noted. Five out of 6 (83%) specimens with a positive or suspicious diagnosis of SCLC were positive for both chromogranin A and TTF-1. Synaptophysin was positive in 3 of 6 (50%) positive or suspicious cases. None of the cases were positive for CK20. All cases with a negative cytologic diagnosis were negative for chromogranin A, synatophysin, CK20, and TTF-1. In conclusion, patients with SCLC rarely present with pleural effusions. The cytology of SCLC is characteristic. The use of immunocytochemistry, particularly with antibodies to chromogranin A, TTF-1, and CK 20, aids in the differential diagnosis. © 2001 Wiley-Liss, Inc.