In humans, interferon γ (IFN-γ) receptor deficiency leads to a predisposition to mycobacterial infections and impairs the formation of mature granulomas. Interleukin-12 (IL-12) receptor deficiency was found in otherwise healthy individuals with mycobacterial infections. Mature granulomas were seen, surrounded by T cells and centered with epithelioid and multinucleated giant cells, yet reduced IFN-γ concentrations were found to be secreted by activated natural killer and T cells. Thus, IL-12–dependent IFN-γ secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas due to IL-12–independent IFN-γ secretion.