We developed a mouse monoclonal antibody, 6E2 (IgG3), against a human embryonal carcinoma (EC) cell line, NCR-G3, that possesses totipotent differentiation capabilities. Culturing human EC cells in the presence of 6E2 causes their death. It has been shown that 6E2 kills EC cells dose dependently. In immunohistochemical examination with normal human germ cells, 6E2 reacted specifically with spermatogonia and oocytes. Among human germ cell tumor tissues on aceton-fixed frozen sections, 6E2 reacted with embryonal carcinomas, seminomas and dysgerminomas, but it did not react with choriocarcinomas or with yolk sac tumors. Consistently, in flow cytometric analysis of cultured human germ cell tumor cell lines, 6E2 reacted exclusively with EC cells including NCR-G3 cells. It was revealed, by preserving its antigenicity after treatment with periodic acid and tunicamycin and by radiolabeling cells followed by immunoprecipitation, that the molecule defined by 6E2 is a cell surface protein having a molecular weight of approximately 80 kDa. These data illustrate that the molecule defined by 6E2 links human germ cell tumors, especially embryonal carcinoma, seminoma and dysgerminoma, to their normal counterparts and that it may play a role in survival and proliferation of human EC cells.