In a multicenter randomized clinical trial by Luyt et al1 published in this issue of JAMA Internal Medicine, twice-weekly screening for oropharyngeal reactivation of herpes simplex virus (HSV) followed by preemptive treatment with acyclovir during 14 days did not increase the number of ventilator-free days at day 60 in patients who received mechanical ventilation in the intensive care unit (ICU). The study informs a debate that has been ongoing for decades regarding the clinical relevance of HSV reactivation in patients without an apparent prior immunocompromised condition.