We have utilized a novel method to generate transgenic mice that are deficient in NK cells. The strategy entails introduction of the H and L chain genes encoding PK136, an antibody shown to be effective in the in vivo elimination of NK cells, into the mouse genome. Since the introduced H chain gene does not contain sequences encoding membrane exons, the transgenic Ig is not expressed on the cell surface, but is secreted by activated B cells. We show that these animals are chronically depleted of NK cells, but not B, T or NKT cells. Therefore, they are compromised in their ability to mediate NK-mediated cytotoxicity. In addition, the deficiency in NK cells reduces the level of switching to various downstream isotypes in response to T-independent type II antigens. However, this reduction is only apparent when antigens are injected in the presence of adjuvant. Since NKT cells are not depleted, the effect cannot be attributed to this subpopulation. These results help to resolve differences in previous findings regarding the role of NK cells in antibody responses.