: Background Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). This pilot prospective randomized clinical trial compares valganciclovir (VGV) to ganciclovir (GCV) as pre‐emptive therapy for CMV viremia in the post‐allogeneic HSCT population. Methods Patients undergoing allogeneic HSCT who were at risk for CMV viremia were monitored post HSCT by weekly quantitative whole blood polymerase chain reaction. Pre‐emptive therapy was delayed until the viral load (VL) was >10,000 copies/mL once, or >5000 copies/mL twice. Patients were randomized to either GCV 5 mg/kg twice a day (b.i.d.) for 7 days followed by daily GCV 5 mg/kg for up to 21 days, or VGV 900 mg b.i.d. for 7 days followed by 900 mg daily for up to 21 days. The primary endpoint was clearance of viremia (VL <5000 copies/mL) within 28 days of initiation of therapy. Result In total, 37 patients were enrolled; 19 patients received treatment with VGV and 18 patients received treatment with GCV. The VGV was not inferior in efficacy to GCV as pre‐emptive therapy, with rates of viral clearance at 28 days of 89.5% and 83%, respectively (P‐value for non‐inferiority = 0.030). Toxicities were similar between the 2 arms. No patients developed CMV disease. Conclusions In this trial, the rates of clearance of viremia appear to be similar with VGV and GCV.