Introduction There is still an ongoing discussion whether a prophylactic or a preemptive therapy against cytomegalovirus (CMV) is superior to reduce the incidence of CMV viremia, acute rejections (AR) and cardiac allograft vasculopathy (CAV) in the long-term after heart transplantation (HTx). Thus, in this study we evaluated different CMV treatmnent strategies in this setting. Materials and Methods In this retrospective study we included 56 patients, who got a HTx between 1st of January 2010 and 31st of July 2016 at our center. Excluded were all patients who died within the first 90 days or who had a loss to follow-up in the first year after HTx. Study end points were the CMV-free survival viremia, AR, CAV and death. The patients were followed up for an average of 4.15 years (355 days up to 7.5 years). Patients were classified into 3 groups according to their received CMV-protocol: preemptive therapy (n=19), prophylactic mono drug therapy (either valganciclovir for average of 110 days or early single dose of 100mg/kg/BW of cytomegaly virus immunoglobulin, CMVIG, within the first two weeks post-HTx, n=18) or prophylactic double drug therapy (valganciclovir for 3 months plus early single dose of CMVIG, n=19). For statistical analysis X2, X2-log-rank and T-Tests were used. Results and Discussion Overall seven patients of our study cohort died (unknown cause n=2, AR n=3, and sepsis n=2). The median patient survival post-HTx was not significant different among the study groups: preemptive group 2243 days, prophylactic monotherapy 2417 days, and prophylactic double therapy 2410 days, respectively (p=0.73). However, the median CMV-viremia free survival was different among the groups: 1817 days in the prophylactic double group, 1459 days in the prophylactic mono group and 1482 in the preemptive group (p=0.52). Especially, in a subanalysis patients with a high risk for CMV infection (donor positive and recipient negative CMV status, n=13) the CMV-free survival was significantly higher when patients received double prophylaxis therapy compared to the other two groups (p<0.01). Whether the incidence of AR nor of CAV was not significantly influenced by the choice of CMV treatment regimen (p=0.87 and p=0.215, respectively). Overall in 15 patients the antiviral medication was discontinuated due to side effects such as leukopenia, preemptive group 10.5%, prophylactic monogroup 38.9%, and prophylactic double group 31.6%, respectively. Conclusion Our study results suggest that early therapy with CMVIG as adjunct to antiviral treatment could prolong CMV-free survival in patients with high risk of CMV infection. If a repetitive CMVIG dosing post-HTx will further reduce CMV infection needs to be explored in the future.