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Reactivation of human herpesvirus 6 (HHV-6) appears to be common after transplant. Viral reactivation may result in febrile illness and may also play an immunomodulatory role that leads to indirect effects such as opportunistic infections and rejection. The objective of this study was to determine the clinical impact of HHV-6 infection after liver transplantation including both direct and indirect effects.This was a prospective single center cohort study of 200 consecutive patients undergoing liver transplantation. Systemic serial HHV-6 viral load measurements and all clinical outcomes including development of opportunistic infections, cytomegalovirus (CMV) disease, and rejection were determined.HHV-6 infection (defined as viral load ≥2 log10 copies/μg input DNA) occurred in 56/200 (28%) patients. Symptomatic disease attributable to HHV-6 alone occurred in 2/200 (1%) patients. Univariate analysis revealed HHV-6 infection was associated with the development of opportunistic infection and CMV disease. In a multivariate analysis designed to control for the level of immunosuppression, the risk of opportunistic infection increased by 3.68-fold in patients with HHV-6 infection (95% confidence interval [CI], 1.86–7.27;P =0.001). In a similar multivariate analysis, the risk of CMV disease increased by 3.59-fold in patients with HHV-6 infection (95% CI, 1.53–8.44;P =0.003). HHV-6 infection was not associated with rejection except in the subgroup of patients with rejection after 30 days posttransplant (odds ration 2.27; 95% CI, 1.09–4.77;P =0.029).HHV-6 reactivation after transplant is common and is associated with the development of opportunistic infections and CMV disease and possibly with a subgroup of acute rejection episodes. HHV-6 infection likely has a significant impact in transplant recipients through indirect effects of viral replication.