Monoclonal antibodies (MAbs) ranked together as small-cell-lung-cancer (SCLC) Cluster I MAbs are directed against the neural cell adhesion molecule NCAM (CD 56) and have been shown to be useful reagents in SCLC diagnosis and therapy. We analyzed the epitopes recognized by 5 SCLC cluster-I MAbs (123C3, 123A8, ERIC-I, MB2, and Leu 19) and a closely related anti CD 56 MAb (T199). Our results show that within the NCAM molecule Ig-like domain 3 and the segment of about 200 amino acids comprised by exons 11-13 are immunodominant regions. The MAbs investigated in this study can be combined into 2 groups. Group 1 consists of MAbs MB2, Leu 19 and T199, which are directed against epitopes located in the 3rd Ig-like domain. These MAbs recognize closely related but distinctive conformational epitopes. MAbs ERIC-1, 123C3 and 123A8 form Group 2 and are directed against a membrane-proximal region of the NCAM molecule. The data presented suggest that the 3 Group-2 MAbs bind to closely related or identical epitopes.