Patients with defects in IFN-γ-or IL-12-mediated immunity are susceptible to infections with Salmonella and non-tuberculous mycobacteria, but rarely suffer from infections with other intracellular pathogens such as Toxoplasma gondii. Here we describe macrophage and T cell function in eight individuals with partial IFN-γ receptor 1 (IFN-γR1) deficiency due to a mutation that results in elevated cell surface expression of a truncated IFN-γR1 receptor that lacks the intracellular domain. We show that various effector mechanisms dependent on IFN-γR signaling are affected to different extents. Whereas TNF-α production was normally up-regulated in response to IFN-γ, IL-12 production and CD64 up-regulation were strongly reduced, and IFN-γ-mediated killing of the intracellular pathogens Salmonella typhimurium and T. gondii was completely abrogated in patient’s macrophages. Since these patients suffer selectively from infections with non-tuberculous mycobacteria and Salmonella, but not T. gondii, despite sero-immunity in six of eight patients, which indicates previous contact with this pathogen, we next studied the role of TNF-α as a possible immune compensatory mechanism. IFN-γ-induced killing of T. gondii appeared to be partially mediated by TNF-α, and addition of TNF-α could compensate for the abrogated killing of T. gondii in the patient’s macrophages. In contrast, IFN-γ-mediated killing of S. typhimurium appeared to be independent of TNF-α. We propose that the divergent role of TNF-α in IFN-γ-induced killing of T. gondii and S. typhimurium may at least partially explain the highly selective susceptibility of patients.