BACKGROUND Antiviral therapy reduces symptom duration and hospitalization risk among previously healthy and chronically ill children infected with seasonal influenza. The effect of oseltamivir on outcomes of hospitalized children is unknown. The primary objective of this study was to determine whether oseltamivir improves outcomes of critically ill children hospitalized with influenza. METHODS We performed a retrospective cohort study of children with influenza infection admitted to a pediatric intensive care unit during 6 consecutive winter seasons (2001-2007). We used the Pediatric Health Information System database, which contains resource utilization data from 41 children's hospitals. We matched oseltamivir-treated patients with oseltamivir-nontreated patients by the probability of oseltamivir exposure using a propensity score we derived from patient and hospital characteristics. We subsequently compared the outcomes of critically ill children treated with oseltamivir within 24 hours of admission with propensity score matched children who were not treated with oseltamivir. RESULTS We identified 1257 children with influenza infection, 264 of whom were treated with oseltamivir within 24 hours of hospital admission. Multivariable analysis of 252 oseltamivir-treated patients and 252 propensity score-matched untreated patients demonstrated that patients treated with oseltamivir experienced an 18% reduction in total hospital days (time ratio: 0.82, P = 0.02), whereas intensive care unit stay, in-hospital mortality, and readmission rates did not differ. CONCLUSIONS For critically ill children infected with seasonal influenza, treatment with oseltamivir within 24 hours of hospitalization was associated with a shorter duration of hospital stay. Additional study is needed to determine the effect of delayed initiation of oseltamivir on clinical outcomes.