We studied the effects of cytomegalovirus (CMV) infection on 301 cardiac transplant recipients who were treated during the cyclosporine era of immunosuppression (1980 to the present). These patients received varying combinations of cyclosporine, azathioprine, prednisone, rabbit antithymocyte globulin, and OKT3 as their immunosuppressive therapy. Two hundred ten patients were free of CMV infection (non-CMV group). During the same period CMV infection developed in 91 patients, as manifested by a fourfold IgG serologic titer rise, demonstration of CMV inclusion bodies in tissue, or positive cultures for the virus (CMV group). The rate of graft rejection was significantly higher in the CMV group. Graft atherosclerosis was significantly more severe in the CMV group as judged by angiographic criteria or by pathologic study. Patient survival rates were significantly lower in the CMV group. Death caused by graft atherosclerosis was significantly more common among patients in the CMV group. Finally, the graft loss rate (from either death or retransplantation for atherosclerosis) was significantly greater in the CMV group. These data demonstrate that CMV infection in cardiac transplant recipients is associated with more frequent rejection, graft atherosclerosis, and death.