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Persistently febrile neutropenic children at risk for invasive fungal infections receive empiric antifungal therapy as a standard of care. However, little is known about the role of echinocandins and liposomal amphotericin B (L-AmB) for empiric antifungal therapy in pediatric patients.Patients between the ages of 2 to 17 years with persistent fever and neutropenia were randomly assigned to receive caspofungin (70 mg/m2 loading dose on day 1, then 50 mg/m2 daily [maximum 70 mg/d]) or l-AmB (3 mg/kg daily) in a 2:1 ratio. Evaluation of safety was the primary objective of the study. Efficacy was also evaluated, with a successful outcome defined as fulfilling all components of a prespecified 5-part composite endpoint. Suspected invasive fungal infections were evaluated by an independent, treatment-blinded adjudication committee.Eighty-two patients received study therapy (caspofungin 56, l-AmB 26), and 81 were evaluated for efficacy (caspofungin 56; l-AmB 25). Outcomes for safety and efficacy endpoints were similar for both study arms. Adverse drug-related event rates [95% confidence interval] were similar between the caspofungin and l-AmB groups (clinical 48.2% [34.7–62.0] versus 46.2% [26.6–66.6]; laboratory 10.7% [4.0–21.9] versus 19.2% [6.6–39.4]). Serious drug-related adverse events occurred in 1 (1.8%) of caspofungin-treated patients and 3 (11.5%) of l-AmB-treated patients. Overall success rates [95% CI] were 46.4% [33.4–59.5] for caspofungin and 32.0% [13.7–50.3] for l-AmB.Caspofungin and l-AmB were comparable in tolerability, safety, and efficacy as empiric antifungal therapy for persistently febrile neutropenic pediatric patients.