To investigate the functional role of interferon (IFN)-gamma in transplant arteriosclerosis, BALB/c hearts were transplanted in immunosuppressed C57BL/6J recipients with (n= 10) or without (n= 10) targeted IFN-gamma gene deletion. In 55-day heart allografts, IFN-gamma deficiency resulted in a significant decrease in vascular thickening. The severity of intimal thickening measured as the percentage of luminal occlusion (mean+/-SEM) in all elastin stained vessels (n= 410) decreased from 37+/-5% in wild-type recipients to 18+/-5% in IFN-gamma-/-recipients (P< 0.005). In the few diseased vessels in grafts from IFN-gamma-/-recipients, the neointima was more cellular with a 90% increase in the nuclear density. This finding correlated with a 50% reduction in fibrosis estimated by alpha-smooth muscle actin cell accumulation in the neointima. The reduction in severity and altered composition of vascular thickening in grafts from IFN-gamma-/-recipients shows that IFN-gamma contributes to arteriosclerotic development following transplantation.