Cytomegalovirus (CMV) is a pathogen of emerging importance for patients with septic shock. In this prospective study, 25 immunocompetent CMV-seropositive patients with septic shock and an intensive care unit stay of > or =7 days were monitored by using quantitative pp65-antigenemia assay, shell vial culture, and virus isolation. Within 2 weeks, active CMV infection with low-level pp65-antigenemia (median 3 positive/5x10(5) leukocytes) developed in 8 (32%) patients. Infection was controlled within a few weeks (median 26 days) without use of antiviral therapy. Duration of intensive care and mechanical ventilation were significantly prolonged in patients with active CMV infection. CMV reactivation was associated with concomitant herpes simplex virus reactivation (p = 0.004). The association between active CMV infection and increased illness could open new therapeutic options for patients with septic shock. Future interventional studies are required.