We have examined the potential of IFN-gamma to ameliorate the physiologic defect of CGD by studying its effects on CGD phagocyte superoxide generation, NADPH-oxidase kinetics, and expression of the gene for the phagocyte cytochrome b heavy chain. In vitro treatment with IFN-gamma increased the respiratory burst activity of PMN and macrophages from three patients in two kindreds with type IA (variant, X-linked). Phagocytes from type I (classic, X-linked) and types IIA and III (autosomal recessive) CGD did not respond to IFN-gamma in vitro. Preliminary studies of in vivo treatment of several of the same patients with subcutaneous IFN-gamma demonstrated similar responses. All subjects whose phagocytes had responded in vitro showed complete or partial correction of the CGD defect in superoxide generation for up to 1 month after IFN-gamma administration. One patient with type I CGD with no detectable in vitro response also showed improved phagocyte respiratory burst activity after in vivo IFN-gamma treatment. These studies establish the potential efficacy of IFN-gamma in the treatment of patients with X-linked CGD and provide an example of pharmacologic modulation of gene expression in human disease. The ease of administration and absence of toxicity suggest a place for IFN-gamma as an adjunct to more conventional antimicrobial therapy during acute infections in CGD and perhaps even other congenital and acquired immunodeficiency states.