Obstructive coronary arterial lesions in the vessels of transplanted hearts result from a complex process in which the immune response of the recipient plays a pivotal role. We have devised an experimental system in which mouse hearts, transplanted after brief treatment with mAbs to CD4 and CD8, survive and contract for many weeks. A high percentage of such hearts develop advanced, obstructive coronary lesions by 4 weeks. Migratory cells of recipient origin localize in the linings of affected vessels, and mediators of inflammation, including adhesion molecules, are present in increased amounts in characteristic locations. Histocompatibility antigen expression is also increased, and these substances may promote the formation of vascular lesions by acting as targets for immune responses. IFN-gamma synthesis has been demonstrated in grafts where it is postulated to be important in the expression of MHC molecules and macrophage activation. Here we report that continuing treatment with R4-6A2, an mAb to IFN-gamma, strikingly inhibits the formation of obstructive vascular lesions in mouse hearts transplanted to recipients incompatible for either class I or class II antigens (P < 0.0001 for the former and P < 0.03 for the latter). Immunohistologic studies showed reduction of the class II-positive mononuclear infiltrate, but focally enhanced endothelial class I expression remained. The mechanism for this effect of anti-IFN-gamma probably extends beyond the influence of anti-IFN-gamma on increased expression of histocompatibility antigens.