Despite prophylaxis, cytomegalovirus (CMV) disease is common in donor seropositive (D+)/recipient seronegative (R-) transplant patients after cessation of prophylaxis. Early detection of CMV may allow for pre-emptive therapy to prevent active disease. The clinical utility of quantitative plasma viral load measurements for predicting CMV disease was determined in 364 D+/R- organ transplant patients receiving prophylaxis (100 d of valganciclovir or oral ganciclovir). Measurements were performed every 2 weeks until day 100 and at months 4, 4.5, 5, 6, 8 and 12 post-transplant. CMV disease occurred in 64 (17.6%) patients by 12 months. Using a positive cut-off value of >400 copies/mL, sensitivity was 38%, specificity 60%, positive predictive value 17%, and negative predictive value 82% for prediction of CMV disease. Therefore, routine monitoring would have predicted disease in only 24/64 (38%) patients. The test characteristics were not improved by changing the viral load cut-off point for defining a positive result. Similarly, single time point measures at the end of prophylaxis or month 4 had low sensitivity for disease prediction. Overall, regular CMV plasma viral load measurements were only of modest value in predicting CMV disease.