We measured the in vitro production of interferon-gamma (IFN-gamma) in five cases of hyper-IgE syndrome (HIgE), induced by mitogens, calcium ionophores and phorbol ester. The biosynthesis of IFN-gamma was severely reduced or undetectable in HIgE, while it was near normal in most atopic patients. The in vitro spontaneous production of IgE was increased overall in HIgE patients, although no correlation was found with serum IgE levels. Recombinant interleukin-4 (IL-4) induced a further increase in IgE synthesis, and its effect was totally antagonized by recombinant IFN-gamma; the same pattern of response was also observed in atopic subjects with high production of IgE. IFN-alpha synergized with IL-4 on IgE synthesis, whereas recombinant IL-6 gave opposite changes in individual cases tested. We propose that IFN-gamma deficiency may be responsible for some of the features of HIgE patients, including IgE levels and infections.