Monoclonal antibodies (MAbs) 126 (immunoglobulin M) and 14.18 (immunoglobulin G3) react strongly with the cell surface of small cell carcinoma of the lungs (SCCL) and are unreactive with most normal tissues and other neoplasms with the notable exception of tumors derived from cells of neural crest origin. These MAbs react specifically with the oligosaccharide portion of the disialoganglioside GD2. Analysis of total gangliosides from cultured cell lines derived from SCCL indicates that GD2 is a predominant ganglioside. A comparison of the reactivities of MAbs against GD2 with those directed against gangliosides GM2 and GD3, each differing from GD2 by a single sugar residue, clearly indicates that GD2 is preferentially expressed by cultured cells derived from SCCL. Membranes isolated from these cells exhibit GD2 synthetase activity which specifically converts the precursor GD3 to GD2 in the presence of uridine diphosphate-N-acetyl galactosamine as the glycosyl donor. We present evidence that in SCCL, GD2 serves as a relevant target antigen for monoclonal antibody-mediated cytolysis. Specifically, we demonstrate that MAb 14.18 (immunoglobulin G3), can lyse small cell carcinoma of the lung targets by either complement- or antibody-dependent cellular cytotoxicity.