Biomaterials are increasingly used for clinical applications. However, loss of function may occur owing to tissue reactions, which are mainly caused by a variety of inflammatory reactions. Recently, we demonstrated that macrophages (MO) and T cells play key roles in these reactions. Since immunological studies showed that the T cell-derived cytokine interferon-gamma (IFN-gamma) activates MO, the aim of this study was to investigate the possibility of modulating tissue reactions to biodegradable biomaterials by inactivating IFN-gamma. Dermal sheep collagen (DSC) was used as a test biomaterial. DSC impregnated with anti-IFN-gamma or phosphate-buffered saline (control) was implanted in rats. The results showed that cellular ingrowth and formation and function of giant cells were strongly delayed by anti-IFN-gamma. Also, MHC class II expression was strongly inhibited. In the treated DSC, some huge giant cells were formed at the interface but association with the DSC bundles did not occur. Finally, in both the control and treated DSC, T cells and NK cells were rarely detected. This study demonstrates that IFN-gamma plays an important role in the inflammatory reaction to biomaterials. This reaction can be modulated by anti-IFN-gamma, which warrants further studies of anti-IFN-gamma for clinical application to prevent unwanted tissue reactions to biomaterials.