OBJECTIVE: Data on complications from upper respiratory infection are limited. We examined development of severe complications in children presenting to the emergency department (ED) for moderate to severe influenza-like illness (ILI). METHODS: Prospective cohort study of children 0 to 19 years presenting to a tertiary care children's hospital ED during peak respiratory viral seasons from 2008 to 2010. Subjects included had moderate to severe ILI, defined by performance of venipuncture and nasopharyngeal multiplex polymerase chain reaction for respiratory viruses. Severe complications (respiratory failure, encephalopathy, seizures, pneumonia, bacteremia, death) were prospectively determined. Risk factors for severe complications were collected, including demographics, comorbidities, and household exposures. RESULTS: There were 241 enrolled subjects with median age of 27.4 months (interquartile range 8.9-68.5); 59.3% were boys and 48.5% were black. High-risk conditions were present in 53.5%. Severe complications developed in 35.3% (95% confidence interval [CI] 29.3-41.3), most frequently pneumonia (26.1%). The risk for severe complications was increased in subjects with neurologic or neuromuscular conditions (relative risk 4.0; 95% CI 1.9-8.2). No specific respiratory virus was associated with development of severe complications. Among patients with influenza, severe complications were greater with subtype H1N1 infection (relative risk 1.45, 95% CI 0.99-2.13, P = .048), and were at highest risk for pneumonia (relative risk 4.2, 95% CI 1.2-15.9). CONCLUSION: In children presenting to the ED for moderate to severe ILI, those with neurologic and neuromuscular disease are at increased risk for severe complications. Development of severe complications did not differ by infecting virus; however, risk of severe complications was greater with subtype H1N1 compared with other influenza.