Novel antigens characteristic of neuroendocrine malignancies. The authors describe the immunochemical detection, biochemical characterization, and tissue distribution of neuroendocrine antigens recognized by three newly developed monoclonal antibodies (MoAb) obtained after immunization of mice with the variant small cell lung cancer (SCLC) cell line NCI-H82. RNL-1 was reactive with neuroendocrine tissues similar to the SCLC cluster-1 MoAb, known to recognize N-CAM. Antibodies RNL-2 and RNL-3 are directed against different epitopes on the same proteinaceous complex. Both MoAb recognize an intracellularly located, water-soluble antigen which has a subunit composition with a protein triplet ranging in molecular weight between 44 and 45 kilodaltons (kD) next to a component of approximately 30 kD. The antibodies RNL-2 and RNL-3 reacted with a subset of neuroendocrine tissues and neuroendocrine neoplasms. In lung cancer both antibodies reacted only with some SCLC and carcinoids and not with nonneuroendocrine lung carcinomas. The potential diagnostic applicability of antibodies RNL-1, RNL-2, and RNL-3 is discussed. 