Diagnostic uncertainty can lead to diagnostic errors, overuse of laboratory and imaging studies, and delays in appropriate treatment. This study reports that diagnostic uncertainty in the pediatric intensive care unit (PICU) was associated with off-hours admission, greater severity of illness, and an atypical presentation. Patients with diagnostic uncertainty had more diagnostic errors in the first 7 days of their PICU stay. 6.6% of patients still had uncertain diagnoses at discharge.