Letermovir, an anti-cytomegalovirus (CMV) drug, is recommended as a prophylactic agent in patients at risk of CMV infection/reactivation after allogeneic hematopoietic stem cell transplant. We report the curative and pre-emptive use of letermovir in two heart transplant recipients. In one patient with ganciclovir-resistant CMV, letermovir was successfully used to treat CMV colitis. In the second patient, letermovir was used as pre-emptive therapy for CMV reactivation, but did not prevent CMV esophagitis. In both cases, letermovir was successful for secondary prophylaxis. Curative use of letermovir may be considered if resistance or major adverse effect of other antivirals therapy is suspected.