Cytomegalovirus (CMV) reactivation is a well-recognised complication of solid organ and stem cell transplantation, causing both direct cytopathology in various organs and indirect immunomodulating effects. However, reactivation also occurs in 14-71% of previously immunocompetent critically ill adults, and although final proof of pathogenicity in such patients is lacking, many studies show that it is independently associated with prolonged mechanical ventilation and death. Two recent RCTs indicated that both valganciclovir and ganciclovir are safe and effective in preventing CMV reactivation in plasma, yet were underpowered to detect meaningful clinical benefit. A much larger trial taking a preemptive approach is expected to report shortly. Thus, based on the available evidence, routine use of anti-CMV prophylaxis in ICU patients who were previously immunocompetent cannot be recommended at this time. However, in patients undergoing a prolonged ICU stay, viral diagnostics and treatment of CMV reactivation may be considered in cases of refractory ARDS or otherwise unexplained organ failure. © 2020, Netherlands Society of Intensive Care. All rights reserved.