In the course of investigating 30 monoclonal antibodies (MAbs) for their potential reactivity with 25 lung tumors of different histologic types, we found that three MAbs commonly used for their specificities for lymphoid markers were highly reactive with non-small-cell carcinomas (NSCLC) and totally nonreactive with small-cell carcinomas (SCLC). Immunostaining was performed by the standard streptavidin-biotin-peroxidase method after microwave antigen retrieval on formalin-fixed, paraffin-embedded tissue sections. LN2 (CD74), LN3 (HLA-DR), and BLA-36, which are commonly used for the identification of B-lymphocytes, strongly immunostained 19 of 25 squamous and adenocarcinomas and none of 34 small-cell carcinomas and carcinoids. Moreover, in combined tumors, these MAbs selectively stained the adenocarcinoma cells but not the adjacent small-cell carcinoma cells. A cocktail mixture of LN2, LN3, and BLA-36 assayed on 24 additional lung tumors produced similar results with even stronger and sharper stainings. Other lymphoid MAbs showed some selective staining but to a lesser degree. Among nonlymphoid MAbs, the results were as expected, with MAbs for cytokeratin (B72.3) and epithelial membrane antigen staining NSCLC but also some SCLC. The MAbs for chromogranin and neuron-specific enolase were not entirely specific, whereas some nerve-cell adhesion molecule MAbs showed good specificity for SCLC. In a field with few specific MAbs, the newly discovered ability of these lymphoid MAbs to dis criminate between SCLC and NSCLC may prove useful in the immunohistochemical diagnosis of lung tumors.