Ganciclovir (GCV)-resistant cytomegalovirus (CMV) infection is a common problem among solid organ transplant (SOT) recipients without prior CMV immunity (CMV D+/R-). GCV-resistant CMV represents a particular challenge for CMV management. Letermovir is a recently licensed antiviral agent for primary CMV prophylaxis in allogenic hematopoietic stem cell transplant (HSCT) recipients. Given the favorable safety profile and its oral bioavailability letermovir may be considered a valuable off-label option for secondary prophylaxis of GCV-resistant CMV in SOT recipients. Here, we describe our experience with letermovir as secondary prophylaxis for GCV-resistant CMV in two renal transplant recipients and review the literature in regard of previously published cases. Letermovir resistance emerged after a few months of secondary prophylaxis in the two renal transplant recipients. In both cases, the previously described UL56 C325Y letermovir resistance mutation was detected. In vitro studies of letermovir suggest a relatively low genetic barrier to resistance. Therefore, caution is warranted when using letermovir as secondary prophylaxis for GCV-resistant CMV infection.