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Background Cytomegalovirus (CMV) infection continues to be a significant contributor to morbidity and mortality among recipients of allogeneic hematopoietic stem cell transplantation (allo HSCT). The introduction of letermovir (LTV) prophylaxis, which blocks the viral terminase complex and consequently prevents the processing of CMV genomic concatemers, has markedly lowered the incidence of CMV infection and reactivation. Despite this progress, the most appropriate strategy for virological surveillance remains uncertain. CMV DNA has been so far the only virological marker, even if there is increasing evidence that its quantification in plasma mainly reflects CMV genomic fragments or concatemers. CMV RNA, targeting UL21.5 mRNA packaged within virions, has recently emerged as a potential tool to better reflect the real burden of virions. On this basis, the present study investigates the kinetics of CMV RNA and CMV DNA during and following LTV prophylaxis.Methods We enrolled 42 onco-hematological patients (pts) undergoing allo-HSCT and receiving LTV prophylaxis for at least 2 months: 30 (71.4%) were monitored after LTV for a median time of 87 [IQR 71–134] days. In total, 464 plasma samples were collected longitudinally and analyzed for CMV DNA and CMV RNA levels using the Elitech assays, with limits of quantification of 112 IU/mL and 30 IU/mL, respectively.Results During LTV prophylaxis, 5 pts (11.9%) exhibited CMV DNA >112 IU/mL (median[IQR]: 296[194–1258]), mostly presenting as single or recurrent blips. None of these individuals showed detectable CMV RNA, suggesting absence of virion production and the release of CMV-DNA concatemers. After discontinuation of LTV, 16 of 30 pts (53.3%) developed CMV DNA >112 IU/mL (median[IQR]: 536[314–3908]); CMV RNA was positive in 5/16 (31.2%). CMV-RNA positivity was associated with higher levels of plasma CMV-DNA (median[IQR]: 12196 [9194-29729] IU/mL in pts with CMV-RNA+ vs 787 [493–2392] IU/mL in pts with CMV-RNA-, p=0.0005) and also with a markedly prolonged duration of CMV DNA detectability (median[IQR]: 129[53–159] days in CMV RNA+ vs 10[7–20] days in CMV RNA-, p<0.0001). This reinforces that transient and low level rises of CMV-DNA do not reflect virion production. Kinetic evaluation during anti CMV treatment revealed a more rapid decline and earlier clearance of CMV RNA, consistent with ongoing release of CMV DNA fragments despite effective suppression of viral particle production.Conclusions CMV RNA offers a more refined interpretation of virological monitoring by differentiating active viral replication from residual genomic material. Its incorporation into clinical practice may support more responsible anti CMV treatment stewardship, reducing overtreatment and mitigating the burden of drug associated toxicity.