The crucial role of interleukin (IL)-4 in the induction of murine IgG1 and IgE responses, which are coupled through the process of sequential isotype switching, has been well documented. Whereas IL-4 is obligatory for the induction of IgE responses, it enhances IgG1 responses. In this study, using neutralizing antibodies, we provide evidence that, besides IL-4, also IL-6 is required for obtaining peak IgG1 responses. The mRNA levels of these two cytokines are coordinately expressed in the spleen of mice immunized with trinitrophenol-keyhole limpet hemocyanin (TNP-KLH). No IL-6 requirement was observed for peak IgE responses. The IL-6 dependence of IgG1 responses was found for both antigen-specific and polyclonal responses. Moreover, it was noted using TNP-KLH and goat anti-mouse (GAM) IgD as antigen that polyclonal IgG1 responses are more dependent on IL-6 than antigen-specific responses. In vitro experiments revealed that exogenous IL-6 neither enhanced nor inhibited the IgG1 and IgE production by naive B cells, suggesting that IL-6 did not interfere with the IL-4-induced isotype switch potential. Primary and memory IgG1 responses were both similarly dependent on IL-6. These observations point to a role of IL-6 in the terminal differentiation of B cells switched to IgG1. Neutralization of IL-6 did not inhibit either antigen-specific or polyclonal IgE responses. Therefore, it was concluded that IL-6 is not involved in the terminal differentiation of B cells switched to IgE. These findings thus provide a distinct role for IL-6, besides IL-4, in regulating murine IgG1 responses. The formation of IgE, however, is completely dependent on IL-4 alone.