Cytomegalovirus (CMV) causes considerable morbidity and mortality in orthotopic liver transplant (OLT) recipients. Several prophylactic strategies against CMV have been studied in solid organ transplant recipients, including cytomegalovirus immune globulin (CMVIG). We examined the effect of CMVIG prophylaxis on first-year and long-term survival after liver transplantation. Data were analysed for 162 OLT recipients from four transplant centers in Boston who participated in two CMVIG prophylaxis trials. Ninety patients received CMVIG (median follow-up 5.6 yr), and 72 patients received placebo (median follow-up 5.4 yr). CMVIG prophylaxis was shown to be associated with increased first-year (86% vs. 72%, p = 0.029) and long-term (68% vs. 54%, p = 0.055) survival. The distribution of baseline characteristics including donor and recipient demographics, donor CMV serostatus, United Network for Organ Sharing (UNOS) status, pre-transplant renal and liver function tests, transplantation surgical time, number of units of blood products administered during transplantation, primary immunosuppressive regimen, use of solumedrol or antilymphocyte therapy for induction of immunosuppression or treatment of rejection, and surgical complications was similar for CMVIG and placebo recipients. CMVIG recipients were more likely to have primary biliary cirrhosis than placebo recipients (21% vs. 8%, p = 0.025). Using a Cox proportional hazards multivariate model to control for pre-transplant liver disease, CMVIG was shown to be independently associated with increased first-year survival (p = 0.042); a trend toward association with increased long-term survival (p = 0.098) was also shown. These data support that CMVIG prophylaxis, beyond its proven efficacy in decreasing the incidence of severe CMV-associated disease, is associated with increased survival when used prophylactically in OLT recipients.