Background: Cytomegalovirus (CMV) infection remains a serious problem after heart transplantation. Recipients with D+/R- CMV serostatus often receive prophylaxis with valganciclovir, but the optimal duration of such therapy after heart transplant is unknown. Methods: We retrospectively reviewed the clinical course of all adult cardiac transplant recipients with D+/R- CMV serostatus at the UT Southwestern Medical Center between January 2003 and December 2006. Standard immunosuppression included basiliximab induction therapy and the CMV prophylaxis included CMV hyperimmune globulin, 2 weeks of intravenous ganciclovir and 3 months of oral valganciclovir. Results: Seven patients met the study criteria. Six of the 7 patients (86%) developed CMV disease. Five of these 6 patients presented with CMV disease within 3 months of the cessation of valganciclovir prophylaxis. Conclusions: There was a high incidence of CMV disease in D+/R- heart transplant recipients despite CMV hyperimmune globulin, 2 weeks of intravenous ganciclovir and 3 months of valganciclovir prophylaxis. CMV infection occurred consistently within 2 to 3 months of cessation of valganciclovir. Alternative strategies for CMV prophylaxis, including an extension of valganciclovir prophylaxis to 6 months after heart transplantation, needs to be investigated.