Interferon-gamma (IFN-gamma), a cytokine that has been shown to upregulate macrophage function, has recently been demonstrated to improve outcome when exogenously administered in several animal models of injury. Because the macrophage is also important in the events that govern wound healing, we evaluated the effects of IFN-gamma upon wound healing in a murine model. IFN-gamma was administered in doses of 937.5-22,500 u synchronous with the creation of a left paraspinous wound and then daily. At Day 10, wounds were harvested, evaluated for wound disruption strength (WDS), and subjected to morphometric analysis. Wounds were also subjected to 36-hr formalin fixation to maximally cross-link collagen fibrils and retested for WDS. We found that IFN-gamma impaired wound healing at all doses relative to control, and WDS was impaired in a dose-dependent fashion. Our highest dose of IFN-gamma (22,500 u) produced a WDS only 65% of the control. Morphometric studies demonstrated less collagen deposition and a lower degree of neovascularity in IFN-gamma-treated animals. In addition, formalin fixation studies suggested that IFN-gamma may impair collagen cross-linking. The potential benefits of IFN-gamma in the multiply injured patient must be weighed against the possibility that IFN-gamma might deleteriously effect events fundamental to wound healing.