The interferon- (IFN-) expression is elicited in response to microbial infections and activates immune surveillance by antimicrobial immune elements to induce microbial killing. Patients with adult-onset immunodeficiency who suffer from recurrent infections with microbes, particularly nontuberculous mycobacteria (NTM), commonly display genetic defects in IFN- signaling as well as the generation of anti-IFN- autoantibodies (autoAbs). Because IFN- is an activator of macrophage differentiation and a proinflammatory activator of innate immunity, the blockade effects of the autoAbs present in NTM patient serum on IFN- are hypothesized to regulate the antimicrobial function of macrophages. In the presence of patient serum, IFN--induced type 1 macrophage (M1) differentiation was inhibited in PMA-stimulated human monocytic THP-1 cells. Treatment with patient serum significantly blocked the production of proinflammatory factors, including cytokines/chemokines and reactive oxygen/nitrogen species, by M1 macrophages. Importantly, IFN--facilitated phagocytosis and degradation of heat-killed mycobacterium were decreased by cotreatment with patient serum. These results show the blockade activity of anti-IFN- autoAbs on IFN--mediated antimicrobial immunity in macrophages.