OBJECTIVE: To determine whether preemptive ganciclovir therapy administered daily during antilymphocyte antibody therapy can prevent cytomegalovirus disease in renal transplant recipients who are positive for cytomegalovirus antibody. DESIGN: Randomized, controlled, multicenter trial. SETTING: 6 university-affiliated transplantation centers. PATIENTS: 113 renal transplant recipients who were positive for cytomegalovirus antibody. INTERVENTION: Patients were randomly assigned to receive either 1) ganciclovir, 2.5 mg/kg body weight administered intravenously on every day that antilymphocyte antibody therapy was administered or 2) no anticytomegalovirus therapy. MEASUREMENTS: Patients were observed for 6 months after completion of antilymphocyte antibody therapy for development of cytomegalovirus disease and cytomegalovirus viremia. RESULTS: Cytomegalovirus disease occurred in 14% of patients (9 of 64) who received preemptive ganciclovir therapy and in 33% of controls (16 of 49) (P = 0.018). Cytomegalovirus was isolated from buffy-coat specimens from 17% of patients (11 of 64) receiving preemptive ganciclovir and from 35% of controls (17 of 49) (P = 0.03). Controlling for the reason (induction or treatment of rejection) for using antilymphocyte antibodies in a Cox proportional hazards model, we found that preemptive ganciclovir still protected against cytomegalovirus disease (adjusted relative risk, 0.27; 95% CI, 0.12 to 0.64). No adverse events were attributed to preemptive ganciclovir therapy during or within 6 months of its administration. CONCLUSIONS: Preemptive ganciclovir therapy administered daily during courses of treatment with antilymphocyte antibodies reduced the excessive occurrence of cytomegalovirus disease in renal transplant recipients who were positive for cytomegalovirus antibody. This approach, which links the most potent immunosuppression to intensive antimicrobial therapy, allows preventive therapy to be given to those patients at greatest risk for developing infectious complications. These patients are likely to benefit most from the preventive strategy.