A wealth of clinical and experimental evidence exists indicating the interaction of cytomegalovirus (CMV) infection and rejection in cardiac allografts. Acute inflammatory response after transplantation leads to release of proinflammatory cytokines that may activate latent CMV infection. In a reciprocal situation, CMV infection leads to up-regulation of transplant antigens and, thereby, to increased immunogenicity and acute rejection. The activation of intragraft mononuclear inflammatory cells and increased mRNA expression of various cytokines and growth factors results in acceleration of the development of chronic rejection. Thus, the effect of CMV infection on cardiac allograft dysfunction isbidirectionalandbiphasic. These two effects of CMV on allograft dysfunction emphasize the need for precise diagnosis of CMV infection in transplant recipients and pre-emptive or prophylactic antiviral therapy. The benefits of this strategy may be evident not only during the early post-transplant period but also, in particular, 5 to 10 years after transplantation as better graft survival.