Background <p>Latent cytomegalovirus (CMV) can reactivate in times of immunosuppression or during critical illness and is associated with worse prognosis, but the benefit of using antiviral medications in otherwise immunocompetent individuals during CMV reactivation is unclear. This study aims to systematically review the effect of using antiviral medications on clinical outcomes in immunocompetent population.</p> Methods <p>Database searches were performed in EMBASE, Medline, Scopus, CINAHL Complete, as well as in two trial registries ClinicalTrials.gov and ICTRP Search Portal. Search terms focused on CMV and antiviral medications among non-immunocompromised hosts admitted to the hospital. Effect estimates were combined using a Random Effects meta-analysis.</p> Results <p>Four randomized controlled trials and two cohort studies were included (total <i>N</i> = 785). There was no significant difference in the use of antiviral medications on composite measure of mortality (<i>p</i> = 0.18) either when given as preemptive treatment or as prophylaxis (<i>p</i> = 0.42), or when subgrouped by randomized studies versus observational studies were compared (<i>p</i> = 0.86). There was no difference in overall intensive care unit length of stay (<i>p</i> = 0.40) or duration of hospitalization (<i>p</i> = 0.25).</p> Conclusion <p>Using antiviral medications in immunocompetent individuals with CMV reactivation did not affect mortality, ICU duration, or hospital duration. No conclusion can be reached regarding decrease in respiratory support post antiviral use.</p> Clinical trial <p>This study is not a clinical trial.</p>