A panel of 12 monoclonal antibodies that preferentially react with human squamous lung carcinoma cells has been produced. All are reactive with fresh frozen sections of squamous cell lung carcinoma tissues in immunoperoxidase assays and are unreactive with lymphoblastoid cells, red blood cells, and fibroblasts in enzyme-linked immunosorbent assay. At least eight of these antibodies interact with cell surface components. These reagents can be subdivided into four groups based upon their reactivities. Groups 1 to 3 are unreactive with normal liver, lung, kidney, colon, spleen, and pancreas in immunoperoxidase assays. Group 1 antibodies (PF1/A, PF1/B, PF1/C, PF1/D, and PF1/E) are all of IgG3 subclass and immunoprecipitate nonsulfated glycoprotein components with molecular weights of 80,000 and 180,000 and a nonglycosylated polypeptide with a molecular weight of 38,000. Group 1 antibodies are also reactive with some lung adenocarcinomas and, with the exception of PF1/E, stain certain differentiated strata within normal adult plantar and fetal epidermis. Group 2 antibodies (PF2/A and PF2/B) react also with breast, gastric, and colonic adenocarcinomas and some tumors of neuroectodermal origin. Group 2 antibodies, which are both of IgG3 subclass immunoprecipitate a nonglycosylated Mr 24,000 polypeptide. Group 3 antibodies (PF3/A, an IgG1; PF3/B, an IgGM; and PF3/C, an IgG2a) react additionally with certain other tumors, as well as with normal adult and fetal epidermis. Group 4 antibodies (PF4/A, an IgG2a; and PF4/B, an IgG1) are less specific than those of the preceding groups, as they react with some normal tissues, including pancreatic islets and pneumocytes, as well as with a variety of adenocarcinomas and tumors of neuroectodermal origin. PF4/A and PF4/B immunoprecipitate Mr 100,000 and 95,000 glycoproteins, respectively.