Survival of Staphylococcus epidermidis inside macrophages has been recognized as a pivotal process in the pathogenesis of biomaterial-associated infection (BAI). Interferon (IFN)-gamma is a potent activator of macrophages. This study examined whether subcutaneous injections of IFN-gamma can reverse macrophage deactivation induced by implanted biomaterials. Mice received subcutaneous implants combined with an injection of 106 S. epidermidis to induce an experimental BAI. Subsequently, 3 groups of mice received subcutaneous injections of 25,000 IU IFN-gamma 3 times weekly, 10,000 IU IFN-gamma 3 times in 2 weeks, or saline 3 times weekly (saline control), respectively. A fourth group received no injections (control). Segments and tissues of the IFN-gamma-treated mice were significantly less (P<.05) culture positive than those of the control groups. Histologically, the high numbers of intracellularly persisting gram-positive cocci observed in the control mice were absent in the IFN-gamma-treated mice. These data indicate that IFN-gamma protects against experimental BAI.