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Recovery from severe burn injury is complicated by infections that are result of immune suppression created by massive inflammatory states. One indication of immune suppression may be activation of viruses like herpes simplex virus (HSV), which may negatively impact recovery. A 5-year retrospective review was performed of adult patients with ≥30% TBSA burn injury. TBSA burn injury, length of hospital stay, ventilator days, mortality, and cultures were reviewed. Twenty-one patients had cutaneous HSV activation (HSV+) and 50 did not (HSV–). Age (44.2 vs 39.8 years) and TBSA burn injury (45.9 vs 45.5%) did not differ between the groups. Length of hospital stay (60.9 vs 39.8 days, P < .05) and ventilator days (34.9 vs 22.2 days, P < .05) were greater in HSV+ patients. HSV activation increased hospital stay (odds ratio [OR] 1.6, confidence interval [CI] 1.08–2.39, P < .05) and mechanical ventilation (OR 1.02, CI 1.00–1.05, P < .05). HSV activation increased the risk of developing positive Acinetobacter baumannii pulmonary cultures (OR 6.4, CI 1.8–22.3, P < .05) and methicillin-resistant Staphylococcus aureus wound cultures (OR 3.3, CI 1.2–9.6, P < .05). HSV activation also increased the risk of developing any positive A. baumannii cultures (OR 9.1, CI 1.9–44, P < .05). HSV activation during severe burn injury is associated with increased length of mechanical ventilation and hospital stay. In addition, these patients have an increased risk of infections from opportunistic bacteria.