Prophylaxis reduces cytomegalovirus (CMV) disease, but is associated with increased costs and risks for side effects, viral resistance and late onset CMV disease. Preemptive therapy avoids drug costs but requires frequent monitoring and may not prevent complications of asymptomatic CMV replication. Kidney transplant recipients at risk for CMV (D+/R−, D+/R+, D−/R+) were randomized to prophylaxis (valganciclovir 900 mg q.d. for 100 days, n = 49) or preemptive therapy (900 mg b.i.d. for 21 days, n = 49) for CMV DNAemia (CMV DNA level >2000 copies/mL in ≥ 1 whole blood specimens by quantitative PCR) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. More patients in the preemptive group, 29 (59%) than in the prophylaxis group, 14 (29%) developed CMV DNAemia, p = 0.004. Late onset of CMV DNAemia (>100 days after transplant) occurred in 11 (24%) randomized to prophylaxis, and none randomized to preemptive therapy. Symptomatic infection occurred in five patients, four (3 D+/R− and 1 D+/R+) in the prophylactic group and one (D+/R−) in the preemptive group. Peak CMV levels were highest in the D+/R− patients. Both strategies were effective in preventing symptomatic CMV. Overall costs were similar and insensitive to wide fluctuations in costs of either monitoring or drug.