Despite broad variability in study populations, methodologies for CMV detection, and analytic methods used, multiple studies have documented frequent CMV infection in non-immunocompromised adults with critical illness due to a variety of causes. Higher rates of CMV infection in studies of seropositive patients suggest that reactivation of latent infection rather than primary infection is the main mechanism in this setting. Risk factors for CMV reactivation (other than seropositivity) have not been clearly defined and there does not appear to be a consistent association with severity of illness. Furthermore, CMV reactivation in this setting has been associated with important adverse clinical outcomes, including increased duration of mechanical ventilation, longer length of stay and all-cause mortality. There are several biologically plausible mechanisms that could link CMV reactivation with adverse outcomes, including: direct lung injury (CMV pneumonia), amplification of inflammation systemically and within the lung, or predisposition to other nosocomial infections, but clinical data in the ICU setting are limited. Further observational studies are unlikely to significantly advance our understanding of the role of CMV in critically ill patients. Given the significant impact of critical illness, limited current therapeutic options, the availability of generally well-tolerated antiviral options for CMV, and the clinical data supporting a possible pathogenic role for CMV, there is a strong rationale for a randomised controlled trial of CMV prevention as a novel means of improving the outcomes of critically ill patients. Copyright © 2010 John Wiley & Sons, Ltd.