Despite demonstrated improvement in patient outcomes with use of the Pediatric Traumatic Brain Injury (TBI) Guidelines (Guidelines), there are differential rates of adherence. Provider perspectives on barriers and facilitators to adherence have not been elucidated. This study aimed to identify and explore in depth the provider perspective on factors associated with adherence to the Guidelines using 19 focus groups with nurses and physicians who provided acute management for pediatric patients with TBI at five university-affiliated Level 1 trauma centers. Data were examined using deductive and inductive content analysis. Results indicated that three inter-related domains were associated with clinical adherence: 1) perceived guideline credibility and applicability to individual patients, 2) implementation, dissemination, and enforcement strategies, and 3) provider culture, communication styles, and attitudes towards protocols. Specifically, Guideline usefulness was determined by the perceived relevance to the individual patient given age, injury etiology, and severity and the strength of the evidence. Institutional methods to formally endorse, codify, and implement the Guidelines into the local culture were important. Providers wanted local protocols developed using interdisciplinary consensus. Finally, a culture of collaboration, including consistent, respectful communication and interdisciplinary cooperation, facilitated adherence. Provider training and experience, as well as attitudes towards other standardized care protocols, mirror the use and attitudes towards the Guidelines. Adherence was determined by the interaction of each of these guideline, institutional, and provider factors acting in concert. Incorporating provider perspectives on barriers and facilitators to adherence into hospital and team protocols is an important step toward improving adherence and ultimately patient outcomes.