Immunohistochemistry is increasingly used as an aid in the diagnosis of small-cell lung carcinoma (SCLC). Previous studies have investigated immunohistochemical staining of SCLC with small numbers of antibodies, but few have examined large series with a broad panel of antibodies. For this reason, the authors examined the distribution and intensity of staining of 20 open-lung biopsy (OLB) and 21 transbronchial biopsy (TBB) specimens of SCLC with a panel of epithelial, neuroendocrine, and hormonal markers. Small-cell lung carcinoma stained most frequently with epithelial markers, followed by neuroendocrine and hormonal markers. Similar percentages of OLB and TBB specimens stained for keratin (100% each) and epithelial membrane antigen (100% and 95%, respectively). Unexpectedly, BER-EP4 stained 100% of OLB specimens. Chromogranin A was the most frequent neuroendocrine marker in OLB and TBB specimens (60% and 47%, respectively) followed by neuron-specific enolase (60% and 33%), Leu-7 (40% and 24%), and synaptophysin (5% and 19%). No neuroendocrine immunohistochemical reactivity was found in 24% of TBB specimens and 20% of OLB specimens. Bombesin was the most sensitive hormonal marker (45% of OLB specimens). These results show that keratin, epithelial membrane antigen, and BER-EP4 are reliable epithelial markers for SCLC in both TBB and OLB specimens. In addition, negative staining for neuroendocrine markers, because it can occur in as many as 25% of cases, should not deter the diagnosis of SCLC.