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Liver transplantation (LT) in critically ill high patients is characterized by septical complications and high mortality rates. In vitro set-ups recently suggested beneficial anti-inflammatory and immunomodulatory capabilities related to cytomegalovirus (CMV) hyperimmunoglobulin (Ig) treatment. Nonetheless, this has not yet been transferred to clinical approaches. We, therefore, performed a clinical trial assessing the impact of early posttransplant therapy with CMVIg on immunology and early outcome in a series of high model of end-stage (MELD) score LT patients.Forty liver transplant patients with a median MELD score of 27 (range: 7-40) at listing and 38 (30 – 40) at LT were included in the analysis. Based on donor/recipient CMV matching, 5000IE CMVIg (Cytotect, Biotest, Germany) was administered (D+ and/or R+) daily for a minimum of one week post-LT. All patients received a tacrolimus (Tac) based immunosuppression. The impact of CMVIg treatment on CMV infection, allograft rejection and serologic parameters of immunologic activation (C-reactive protein [CRP]; procalcitonin [PCT]; interleukin 6 [IL-6]) was assessed. Prognosticators of 3-months survival were assessed by uni- and multivariate analysis.At LT, 18 patients were under renal replacement therapy (45%), 24 patients had to be ventilated (47.2%), and 24 patients received catecholamines (60%). Fatal risk triad (ventilation + dialysis + catecholamines) was present in 14 patients (35%). 24 patients received CMVIg (60%) post-LT, whereas 16 patients did not. Post-LT rates of CMV viremia and biopsy proven allograft rejection were 0% in the CMVIg- but 37% in the non-CMVIg group (p=0.001), although peak Tac levels were comparable (11.1 vs. 12.3 μg/L). Posttransplant mean peak values of CRP (4.9 vs. 16.3 mg/dl; p < 0.001), PCT (10.5 vs. 71.2 ng/ml; p < 0.001) and Il-6 (91.7 vs. 333.1 pg/ml; p < 0.001) were significantly lower in the CMVIg subset. Neutropenia post-LT was evident in 5 CMVIg patients (20.8%) and in 11 patients without CMVIg (69%; p = 0.002). 3-months survival rates were 95.5% and 62.5% in the CMVIg- and non-CMVIg subsets, respectively (log rank < 0.001). Septical complications were the major reason for mortality. In multivariate analysis, only CMVIg treatment (HR=6.0; 95%CI 2.09 – 17.35; p = 0.001) and absence of MMF (HR=0.268; 95%CI 0.096 – 0.753; p = 0.012) were assessed as independent and significant predictors of beneficial survival.Early posttransplant treatment of CMVIg reduces pro-inflammatory and immunologic activation in critically ill liver transplant patients. Thereby, risk of CMV infection, allograft rejection and septical complications seem to be reduced. Our data clearly suggest that CMVIg provides balancing immunoregulatory efficacies, which may be particularly beneficial in high MELD liver recipients.