BACKGROUND: Late-onset CMV disease is being increasingly recognized as a significant post-transplantation complication. OBJECTIVES: To discern the impact of antiviral prophylactic strategies on the emerging syndrome of late-onset CMV disease in organ transplant recipients. STUDY DESIGN: Review of existing reports and published data relevant to antiviral prophylaxis in organ transplant recipients. RESULTS: Prevention of CMV using prophylaxis has proven effective and is widely employed in organ transplant recipients. However, late-onset CMV disease is increasingly being recognized as a significant complication in these patients. The more potent the activity of the antiviral drug and the longer duration of prophylaxis, the greater likelihood of late-onset CMV disease. CMV seronegative recipients of seropositive donor allografts appear to be at a uniquely high risk. A higher proportion of patients with late-onset CMV have tissue invasive disease. Late-onset CMV disease in liver transplant recipients conferred an independently higher risk of mortality in the first post-transplant year. Prolonged antiviral therapy may impair the recovery of CMV-specific T-cell responses. Preemptive therapy appears to be less likely to be associated with CMV disease. CONCLUSIONS: Discernment of the pathophysiologic basis of late-onset CMV warrants investigation. Preemptive therapy may be the preferable approach to CMV prophylaxis.