Efforts to prevent relapsed cytomegalovirus (CMV) disease among solid organ transplant (SOT) recipients present clinical challenges. Historically, SOT recipients treated with short courses of ganciclovir, without documented clearance of viremia, had relapse rates of 23-33%. Current treatment often includes much longer courses of valganciclovir, and persistence of viremia at the end of treatment is rare. We sought to determine the rate and risk factors for relapse under those treatment conditions. Records of 1760 SOT recipients from January 2003 to June 2007 were reviewed; 105 cases of CMV viremia were identified. Relapse occurred in 20/105 (19%); 50% had end-organ disease at the time of relapse. Most patients received approximately 3 months of valganciclovir. Clearance of viremia was documented in 19/20 patients with relapse. Multivariable analysis identified receipt of a thoracic organ and diabetes mellitus as risk factors for relapse. Despite long treatment courses with valganciclovir and documented clearance of viremia, CMV relapse remains common among SOT recipients. Better understanding of the epidemiology of CMV among SOT recipients and validation of risk factors for disease relapse should be the focus of future prospective trials. Such trials should include different treatment durations and extended monitoring for relapse.