A randomized trial comparing a DNAemia cutoff of 10 000 copies per ml whole blood and first pp65 antigenemia positivity for initiation of preemptive therapy of human cytomegalovirus (HCMV) infection in adult hematopoietic stem cell transplant recipients was completed. DNAemia was chosen for cutoff definition since it is more automatable and standardizable than antigenemia, and more closely reflects the actual viral replication. The primary end point of the study was to compare the number of patients treated in the two arms. A total of 83 patients (42 in the DNAemia, and 41 in the antigenemia arm) were enrolled in the study. The incidence of HCMV infection, as detected by the relevant randomization assay (76% in the DNAemia versus 85% in the antigenemia arm), was comparable in the two arms, whereas the number of patients treated was significantly lower in the DNAemia arm (63 versus 80%, P=0.02). A single patient in the DNAemia arm suffered from biopsy-proven HCMV gastric disease diagnosed in the absence of detectable virus in blood. The incidence of graft-versus-host disease, and transplantation-related mortality did not differ between the two arms. In conclusion, our study shows that the use of a cutoff significantly reduces the number of patients requiring antiviral treatment, thus sparing unnecessary drug administration.