Cytomegalovirus (CMV) disease in liver transplant patients with donor-seronegative and recipient-seronegative (D-/R-) status is a rarity. Ganciclovir-resistant CMV disease in this population has not been reported in the literature. We present a 62-year-old man who underwent orthotopic liver transplant from a cadaveric donor. The patient's status was CMV D-/R-, and he had completed 90 days of valganciclovir therapy for CMV prophylaxis, yet he developed CMV disease. We highlight the danger of the liberal use of CMV prophylaxis in this subset of the liver transplant population. To our knowledge, this is the first report of ganciclovir-resistant (GanR) CMV disease in a liver transplant patient with CMV D-/R- status.