Abstract Background Chronic infection with hepatitis E virus (HEV) has recently been recognized in immunocompromised or immunosuppressed individuals. Case Report We report a case of concurrent HEV and human herpes virus-6 (HHV-6) infection, documented by serum HEV RNA and HHV-6 DNA, in an orthotopic liver transplant (OLT) recipient in the United States, where HEV genotype 3 infection, although prevalent, is considered to be self-limited and almost always asymptomatic. The coinfection was accompanied by elevated serum aminotransaminases, liver biopsies demonstrating chronic hepatitis, and the presence of HEV RNA in the tissue. After lowering of immunosuppressive therapy and 2 courses of valganciclovir, sequential clearance of the viruses and normalization of the serum aminotransaminases were observed. Conclusions HEV infection can lead to chronic hepatitis in OLT recipients, and evaluation of this virus should be considered in immunosuppressed individuals with unexplained liver test abnormalities.