OBJECTIVES Cytomegalovirus is the most common viral infection after orthotopic liver transplant. The purpose of the present study was to determine the incidence of cytomegalovirus reactivation in Iranian liver transplant recipients at our center and to evaluate outcomes with preemptive therapy with ganciclovir for pp65 antigenemia. MATERIALS AND METHODS There were 145 patients who had liver transplant and who survived > 2 weeks after transplant. All patients were evaluated for pp65 antigenemia weekly until 90 days after transplant. The diagnosis of cytomegalovirus reactivation was made when a recipient had pp65 antigenemia ≥ 1/50,000 leukocytes. In patients who had cytomegalovirus infection, preemptive therapy with ganciclovir (5 mg/kg, intravenous, twice daily) was started immediately after diagnosis and continued for ≥ 21 days and until cytomegalovirus antigen became undetectable on 2 consecutive tests. RESULTS All patients in our study were seropositive for cytomegalovirus before transplant. Follow-up at mean 27 ± 20 months (range, 5.2 to 80.6 mo) after transplant showed that 46 patients (32%) had cytomegalovirus reactivation at mean 56 ± 67 days after transplant (range, 12 to 445 d). There was a higher frequency of female patients in the cytomegalovirus reactivation than non-reactivation group (odds ratio, 2.3; P ≤ .02). The most common causes of liver failure in the cytomegalovirus reactivation group were autoimmune hepatitis, cryptogenic cirrhosis, and hepatitis B virus cirrhosis. There was no significant relation between cause of liver failure, use of steroids before or after transplant, and frequency of acute rejection and cytomegalovirus reactivation. Only 1 patient (2%) developed cytomegalovirus disease at 22 days after transplant, and this patient was treated successfully. There were 6 patients (13%) who developed a second episode of cytomegalovirus reactivation at median 43 days (range, 10 to 176 d) after the first episode; all 6 patients were treated successfully with ganciclovir. CONCLUSIONS Preemptive treatment with ganciclovir may be an effective approach against cytomegalovirus in seropositive recipients after liver transplant.