Objective The relationship between acute care clinical indicators in the first severe Pediatric traumatic brain injury (TBI) Guidelines and outcomes have not been examined. We aimed to develop a set of acute care guideline-influenced clinical indicators of adherence and tested the relationship between these indicators during the first 72 hours after hospital admission and discharge outcomes. Design Retrospective multicenter cohort study Setting Five regional pediatric trauma centers affiliated with academic medical centers. Patients Children under 17 years with severe TBI (admission Glasgow coma scale (GCS) score ≤ 8, ICD-9 diagnosis codes of 800.0-801.9, 803.0-804.9, 850.0-854.1, 959.01, 950.1-950.3, 995.55, maximum head abbreviated injury severity score ≥ 3) who received tracheal intubation for at-least 48 hours in the intensive care unit (ICU) between 2007 -2011 were examined. Interventions None Measurements and Main Results Total percent adherence to the clinical indicators across all treatment locations (pre-hospital [PH], emergency department [ED], operating room [OR], and intensive care unit [ICU]) during the first 72 hours after admission to study center were determined. Main outcomes were discharge survival and Glasgow outcome scale (GOS) score. Total adherence rate across all locations and all centers ranged from 68-78%. Clinical indicators of adherence were associated with survival (aHR 0.94; 95 % CI 0.91, 0.96). Three indicators were associated with survival: absence of PH hypoxia (aHR 0.20; 95% CI 0.08, 0.46), early ICU start of nutrition (aHR 0.06; 95% CI 0.01, 0.26), and ICU PaCO2 >30 mm Hg in the absence of radiographic or clinical signs of cerebral herniation (aHR 0.22; 95% CI 0.06, 0.8). Clinical indicators of adherence were associated with favorable GOS among survivors, (aHR 0.99; 95% CI 0.98, 0.99). Three indicators were associated with favorable discharge GOS: all OR CPP >40 mm Hg (aRR 0.64; 95% CI 0.55, 0.75), all ICU CPP > 40mm Hg (aRR 0.74; 95% CI 0.63, 0.87), and no surgery (any type; aRR 0.72; 95% CI 0.53, 0.97). Conclusions Acute care clinical indicators of adherence to the Pediatric Guidelines were associated with significantly higher discharge survival and improved discharge GOS. Some indicators were protective, regardless of treatment location, suggesting the need for an interdisciplinary approach to the care of children with severe TBI.