The antigen dose-dependent production of IgE versus IgG2a antibodies has been investigated using keyhole limpet hemocyanin (KLH) and bee venom phospholipase A2 (PLA2) as antigens. Repeated injections of minute doses (0.1 microgram/mouse) of KLH into CBA/J mice lead to relatively high titers of IgE antibodies which are gradually reduced in animals that had received higher doses of antigen. In contrast, the IgG2a antibody titers are inversely correlated, resulting in low titers after repeated injection of 0.1 microgram KLH and high titers after repeated doses of 10 micrograms/mouse. With PLA2 as antigen, one finds a comparable dose-dependent downregulation of IgE antibody production. In contrast to the response to KLH, there is, however, only a marginal IgG2a response at all doses tested, and no dose-dependent increase can be found. The data show that an inverse regulation of IgE and IgG2a responses is not mandatory. Instead there seems to be an additional regulation dictated by antigen epitopes.