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Objective To investigate the efficacy and safety of posaconazole (PCZ) in the prevention of invasive fungal disease (IFD) during allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods The medical records of 80 patients who received allo-HSCT at our center from March 2017 to March 2021 were retrospectively reviewed and analyzed. They were accordingly divided into PCZ group (n=50) and control group (n=30, taking other anti-fungal drugs). The efficacy and safety of PCZ was analyzed in the prevention of IFD. Results In the PCZ group, 6 patients (12.0%) developed IFD, including 2 confirmed cases and 4 clinically diagnosed. While, IFD occurred in 14 cases from the control group, including 6 confirmed, 6 clinically diagnosed and 2 suspected cases. The incidence of IFD was significantly lower in the PCZ group than the control group (P=0.001). Moreover, in the PCZ group, 38 patients (10.5%) with primary prevention developed 4 cases of IFD, and 2 cases (16.7%) of IFD occurred in 12 patients of secondary prevention, showing no significant difference in the IFD incidence (P=0.951). The IFD-related mortality (21.0% vs 61.5%, P=0.030) and rate of abnormal liver function (20.0% vs 46.7%, P=0.012) were both significantly lower in the PCZ group than the control group. Conclusion PCZ is effective in the prevention of IFD during allo-HSCT, and reduces IFD-related deaths and occurrence of adverse reactions.