Late-onset cytomegalovirus (CMV) disease is a significant problem in D+/R− solid organ transplant (SOT) patients who receive antiviral prophylaxis. We assessed the clinical utility of CMV IgG and IgM serology testing for predicting late-onset CMV disease. We evaluated 352 D+/R− transplant recipients who participated in a trial comparing 100 days of ganciclovir versus valganciclovir prophylaxis. CMV serology was assessed on day 28, 56, 100, and 6 and 12 months post-transplant. IgG seroconversion occurred in 26.9% of patients by day 100, and in 63.4% and 75.3% by 6 and 12 months, respectively. IgM seroconversion occurred in 8.3%, 41.8% and 54.9% by day 100, month 6 and month 12, respectively. Seroconversion by day 100 (end of prophylaxis) was not predictive of subsequent CMV disease (CMV disease 13.3% if seropositive vs. 17.8% if seronegative; p = NS). However, at 6 months post-transplant, IgG serostatus was predictive of subsequent CMV disease between month 6 and 12 (CMV disease 1.3% if seropositive vs. 10.0% if seronegative; p = 0.002). In D+/R− patients, CMV serology testing is for the most part not clinically useful for predicting subsequent disease. However, seroconversion by 6 months may be useful for identifying patients at risk of late-onset CMV disease.