The normal sera of several mouse strains contained cytotoxic activity toward lymphocytes treated with neuraminidase (Nase) but not to untreated cells. The greatest cytotoxic activity was in C3H/HeJ mice. CBA/J and AKR/J mice also had high levels. In C57BL/6J mice, there was no cytotoxic activity toward Nase-treated lymphocytes. This cytotoxic activity (probably antibody) was complement dependent and stable at 56° C for 30 minutes, but was inactivated by heating to 80° C for 30 minutes. Nase-treated C3H/HeJ and C57BL/6J cells contained equal amounts of this “hidden” antigen, as determined by absorption studies. Untreated cells contained no detectable antigen. These natural antibodies to a “cryptic” antigen exposed by Nase treatment were the basis of a theory to explain the increased immunogenicity of Nase-treated cells.