We present a case report of a cytomegalovirus (CMV)-seronegative, 58-year-old male who received a CMV-seropositive donor liver transplant without CMV prophylaxis. On postoperative day 30, the patient developed primary CMV disease that responded to ganciclovir. On postoperative day 114, however, he was diagnosed with recurrent CMV infection. Despite aggressive, combined antiviral treatment with ganciclovir and foscamet and reduction of immunosuppression, viral clearance was never achieved. Serum samples were collected throughout the infectious process for viral DNA analysis. Portions of the UL97 and UL54 genes were amplified and compared to the AD169 wild-type strain. Sequencing studies revealed the presence of mutations in viral isolates obtained after clinical resistance was observed. These mutations were not present in samples obtained during the primary CMV infection. Our findings suggest the presence of coinfection with at least 2 different strains of CMV rather than induction of mutations after ganciclovir therapy. © 2007 AASLD.