Letermovir is a recently approved antiviral shown to decrease clinically significant cytomegalovirus (CMV) infection after hematopoietic cell transplantation (HCT) in a phase 3, randomized, placebo-controlled trial. Appearing in Blood, the authors make two key points: 1) Letermovir prophylaxis may be associated with decreased polyfunctional CMV-specific T-cell immunity after HCT, and 2) COMPASS is an analytical tool that can effectively measure polyfunctional CMV-specific T-cell immune responses.