OBJECTIVE: To describe the risk factors for acquiring functional or cognitive disabilities during admission to a PICU. DESIGN: Retrospective analysis of a multicenter PICU database. SETTING: Twenty-four PICUs in the Virtual PICU Performance System network from January 1, 2009, through December 31, 2010. PATIENTS: Consecutive patients, who are 1 month to 18 years old, who survived to discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were acquired global functional disability and cognitive disability during admission to a PICU, measured by change in Pediatric Overall Performance Category or in Pediatric Cerebral Performance Category scores, respectively. The primary analysis cohort consisted of 29,352 admissions to the 24 Virtual PICU Performance System sites which collected the main outcome variables. Respectively, 10.3% and 3.4% of the cohort acquired global functional or cognitive disability. Trauma diagnosis (odds ratio, 4.50; 95% CI, 3.83-5.29; odds ratio, 3.91; 95% CI, 3.07-4.98), unscheduled admission to the PICU (odds ratio, 2.67; 95% CI, 2.27-3.12; odds ratio, 1.52; 95% CI, 1.16-2.00), highest risk of mortality category (odds ratio, 1.19; 95% CI, 1.02-1.39; odds ratio, 2.70; 95% CI, 2.15-3.40), oncologic primary diagnoses (odds ratio, 5.61; 95% CI, 4.56-6.91; odds ratio, 4.30; 95% CI, 2.97-6.24), and neurologic primary diagnoses (odds ratio, 2.04, 95% CI, 1.70-2.44; odds ratio, 4.29, 95% CI, 3.18-5.78) were independently associated with acquiring both functional and cognitive disability. Intervention risk factors for acquiring both functional and cognitive disability included invasive mechanical ventilation (odds ratio, 1.79; 95% CI, 1.60-2.00; odds ratio, 2.83; 95% CI, 2.36-3.39), renal replacement therapy (odds ratio, 2.43; 95% CI, 1.73-3.42; odds ratio, 1.76, 95% CI, 1.08-2.85), cardiopulmonary resuscitation (odds ratio, 1.91; 95% CI, 1.24-2.95; odds ratio, 1.81; 95% CI, 1.02-3.23), and extracorporeal membrane oxygenation (odds ratio, 7.40, 95% CI, 4.10-13.36; odds ratio, 14.04, 95% CI, 7.51-26.26). CONCLUSIONS: We identified a subset of patients whose potential for acquiring global functional and cognitive disability during admission to the PICU is high. This population may benefit from interventions that could mitigate this risk and from focused follow-up after discharge from the PICU.