Interleukin-12(IL-12) promotes cell-mediated Th1 responses and production of IFN-γ that downregulates IgE production. The signal of IL-12 is transduced through the IL-12 receptor (IL-12R) and Stat4. Twenty-four of 75 atopic individuals with high levels of IgE showed insufficient IFN-γ production by peripheral blood mononuclear cells (PBMCs) following stimulation with IL-12 but not that with phytohemagglutinin (PHA). Interestingly, 10 of the above 24 subjects were found to be heterozygous for truncated (2496 del 91) or missense (1577 A to G and 2799 A to G) mutations of IL-12R β2 chain gene (IL-12R β2). Insufficient phosphorylation of Stat4 was also demonstrated in these 10 individuals. This is the first report showing that reduced IFN-γ production following IL-12 stimulation is associated with the heterozygous IL-12R β2 mutations in atopic subjects.