Seropositive umbilical cord blood transplant (UCBT) recipients are at increased risk for CMV complications. To reduce CMV complications, we adopted an intensive strategy that consisted of ganciclovir administered before transplantation (5 mg/kg intravenously daily from day -8 to day -2), high-dose acyclovir (2 g, 3 times daily) after transplantation, and biweekly monitoring with a serum CMV PCR for preemptive therapy. Hazard rates and cumulative incidence of CMV complications along with days treated were compared in high-risk CMV-seropositive UCBT recipients who received the intensive strategy and a historical cohort who received a standard strategy. Of 72 seropositive patients, 29 (40%) received standard prophylaxis and 43 (60%) the new intensive approach. The hazard rate (HR) for CMV reactivation was lower for patients receiving the intensive strategy (HR 0.27, 95% confidence interval 0.15-0.48; P < .001) and led to fewer cases of CMV disease by 1 year (HR 0.11, 95% confidence interval 0.02-0.53; P = .006). In patients who reactivated, the intensive strategy also led to fewer days on CMV-specific antiviral therapy (median 42% [interquartile range 21-63] vs 70% [interquartile range 54-83], P < .001). Use of an intensive CMV prevention strategy in high-risk CMVseropositive UCBT recipients results in a significant decrease in CMV reactivation and disease.