Antibodies have found application in the diagnosis and therapy of cancer. These antitumor antibodies are confined to isotypes of IgG and little is known of the potential usefulness of other classes of immunoglobulin. In order to determine a possible antitumor effect of IgE antibody a tumor-specific mouse monoclonal IgE antibody was constructed. This antibody was derived from the mouse monoclonal antibody 30.6 that detects an antigenic determinant expressed on the surface of colorectal adenocarcinoma cells, including COLO 205. Mouse IgE 30.6 inhibited the growth of established COLO 205 tumor growing subcutaneously in scid mice. This effect was transient with tumor growth returning to pretreatment levels after 48 h. By contrast, a mouse IgG 30.6 and a chimeric human/mouse IgE 30.6 were without antitumor effect. This isotype-specific antitumor effect was not attributable to differences in antibody affinity, tumor localization, or serum half-life as these were essentially the same for all three isotypes of antibody. In addition, none of the 30.6 monoclonal antibodies inhibited the growth of COLO 205 cells in vitro. As little as 1 microgram per mouse of the tumor-specific mouse IgE antibody was sufficient to inhibit COLO 205 tumor growth, which is in contrast to previous results in which the comparatively weak antitumor effect of a chimeric human/mouse IgG1 required an optimum dose of 4 x 250 micrograms per mouse. This antitumor effect of mouse IgE 30.6 was specifically abrogated by prior administration of a nonspecific mouse IgE. Given this potency, and the fact that mouse Fc epsilon RI binds mouse IgE, but not human IgE, a role for Fc epsilon receptor bearing effector cells in the observed antitumor effect is discussed.