Background The VIPP study compared valganciclovir prophylaxis with preemptive treatment regarding efficacy, safety, and long-term graft outcome in cytomegalovirus (CMV)-positive (R+) renal transplant recipients. Methods Multicenter, open-label, randomized clinical study with a 12-month study phase and a follow-up of up to 84 months. Patients in the prophylaxis group received 2 × 450 mg/d oral valganciclovir for 100 days adjusted to renal function. Preemptive treatment with 2 × 900 mg/d valganciclovir was initiated at a viral load of 400 CMV copies/mL or greater (polymerase chain reaction) and maintained over ≥14 days, followed by secondary prophylaxis. Patients were stratified by donor CMV IgG serostatus (donor CMV IgG positive [D+]/R+, donor CMV IgG negative [D-]/R+). Results The 12-month results were reported previously (Witzke et al Transplantation 2012). The intent-to-treat/safety population comprised 148 patients in the prophylaxis (61.5% D+/R+) and 151 patients in the preemptive group (52.3% D+/R+). Overall, 47% patients completed the follow-up. Significantly fewer patients in the prophylaxis compared with preemptive group experienced a CMV infection or disease up to month 84 (11.5%; 95% confidence interval [95% CI], 6.8-17.8%] vs 39.7%; 95% CI, 31.9-48.0%; P < 0.0001 and 4.7%; 95% CI, 1.9-9.5% vs 15.9%; 95% CI, 10.5-22.7%; P = 0.002). Incidences of graft loss (7.4% vs 8.6%), death (9.5% vs 11.3%), rejection (29.1% vs 28.5%), and renal function (estimated glomerular filtration rate [mean ± SD]: 58.2 ± 26.3 vs 59.9 ± 25.7 mL/min per 1.73 m2) were not significantly different between prophylaxis and preemptive treatment. Tolerability was comparable between groups. Conclusions Prophylaxis was more effective than the preemptive approach, applying a low-intense surveillance protocol in preventing CMV infection and disease in intermediate-risk patients. Both strategies were similarly effective in preventing graft loss and death under the conditions of this long-term trial with a threshold of 400 copies/mL for initiation of anti-CMV treatment.