Background. Systemic reactivations of herpesviruses may occur in intensive care unit (ICU) patients, even in those without prior immune deficiency. However, the clinical relevance of these events is uncertain. Methods. In this study we selected patients admitted with septic shock and treated for more than 4 days from a prospectively enrolled cohort of consecutive adults in the mixed ICUs of 2 tertiary care hospitals in the Netherlands. We excluded patients who had received antiviral treatment in the week before ICU admission and those with known immunodeficiency. We studied viremia episodes with cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), and varicella zoster virus (VZV) by weekly polymerase chain reaction in plasma. Results. Among 329 patients, we observed 399 viremia episodes in 223 (68%) patients. Viremia with CMV, EBV, HHV-6, HSV1, HSV-2, and VZV was detected in 60 (18%), 157 (48%), 80 (24%), 87 (26%), 13 (4%), and 2 (0.6%) patients, respectively; 112 (34%) patients had multiple concurrent viremia events. Crude mortality in the ICU was 36% in this latter group compared to 19% in remaining patients (P < .01). After adjustment for potential confounders, time-dependent bias, and competing risks, only concurrent CMV and EBV reactivations remained independently associated with increased mortality (adjusted subdistribution hazard ratio, 3.17; 95% confidence interval, 1.41-7.13). Conclusions. Herpesvirus reactivations were documented in 68% of septic shock patients without prior immunodeficiency and frequently occurred simultaneously. Concurrent reactivations could be independently associated with mortality.