Objective: To evaluate the efficacy and safety of prophylactic antifungal therapy in reducing invasive fungal infections (IFIs) and improving clinical outcomes in critically ill patients with severe burn and trauma. Methods: A multicenter randomized controlled trial was conducted on 426 patients with severe burn (total body surface area [TBSA] ≥ 30%) or polytrauma (Injury Severity Score [ISS] ≥ 25) admitted to 12 Level 1 trauma and burn centers across the United States from January 2022 to March 2025. Patients were randomly assigned to the prophylactic antifungal group (n=213, fluconazole 400 mg/day intravenously for 14 days) and the control group (n=213, placebo). The primary outcome measure was the incidence of proven or probable IFIs within 28 days of admission, diagnosed according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. Secondary outcomes included 28-day and 90-day all-cause mortality, length of intensive care unit (ICU) stay, total hospital stay, and incidence of adverse drug reactions. Results: The incidence of IFIs was significantly lower in the prophylactic antifungal group than in the control group (8.9% vs. 22.1%, P<0.001). The most common IFIs in the control group were candidemia (12.2%) and invasive pulmonary aspergillosis (5.6%). The 28-day mortality rate was 15.5% in the prophylactic antifungal group and 26.3% in the control group (P=0.002), while the 90-day mortality rate was 21.1% and 32.4% respectively (P=0.003). Multivariate logistic regression analysis confirmed that prophylactic antifungal therapy was an independent protective factor for IFIs (OR=0.32, 95% CI=0.17–0.60, P<0.001) and 28-day mortality (OR=0.46, 95% CI=0.27–0.79, P=0.005). The prophylactic antifungal group also had shorter mean ICU stay (22.5 ± 6.8 days vs. 28.7 ± 8.2 days, P<0.001) and total hospital stay (38.2 ± 9.5 days vs. 46.5 ± 11.3 days, P<0.001). The incidence of adverse drug reactions (including hepatotoxicity and electrolyte disturbances) was comparable between the two groups (7.5% vs. 6.1%, P=0.486). Conclusion: Prophylactic antifungal therapy with fluconazole significantly reduces the incidence of IFIs and improves survival in critically ill patients with severe burn and trauma, with a favorable safety profile. This intervention should be considered as a standard component of care for this high-risk population