Ganciclovir prophylaxis reduces the risk of CMV infection and disease in high risk kidney recipients, but its administration form and dosage is still of controversy. Our study was designed to compare the efficacy and safety of two different regimens of oral and intravenous Ganciclovir in high risk kidney recipients. Thirty-four CMV-seropositive kidney recipients from seropositive donors who had undergone antilymphocytic immunosuppressive therapy were assigned randomly into two groups of oral (1000 mg, TID, 12 weeks) and intravenous (5 mg/kg, 2 weeks) Ganciclovir prophylaxis. Doses were adjusted for renal impairment. Follow-up was performed for 12 months and patients were evaluated for clinical and laboratory outcomes regarding CMV serostatus, CMV disease, graft outcome, and Ganciclovir side effects. Sixteen patients in the oral group and 14 ones in the IV group completed the study. CMV infection occurred in 6 (37.5%) and 5 (35.7%) of the cases in oral and IV groups, respectively (p=NS). The mean interval between prophylaxis initiation and the first positive CMV Ag result was 3±2.19 months, with no significant difference between the two groups (p=0.6). Only 2 patients in the IV group experienced CMV disease which were not tissue invasive (p=0.2). Acute rejection was observed in 9 out of 30 recipients, but it did not have any association with prophylaxis regimen or CMV serostatus. The patients well tolerated oral Ganciclovir and the compliance percent was 81.6%. No complication was reported either. According to our findings, oral and IV Ganciclovir had no significant difference in the reduction of CMV infection rate in high risk kidney recipients. Oral Ganciclovir was also effective and safe in the prevention of CMV disease. Moreover, it seems that CMV infection is not associated with acute rejection.