BACKGROUND: Evidence-based standards for management of the seriously sick child have existed for decades, yet their translation in clinical practice is a challenge. The context and organization of institutions are known determinants of successful translation, however, research using adequate methodologies to explain the dynamic nature of these determinants in the quality-of-care improvement process is rarely performed. METHODS: We conducted mixed methods research in a tertiary hospital in a low-income country to explore the uptake of locally adapted paediatric guidelines. The quantitative component was an uncontrolled before and after intervention study that included an exploration of the intervention dose-effect relationship. The qualitative component was an ethnographic research based on the theoretical perspective of participatory action research. Interpretive integration was employed to derive meta-inferences that provided a more complete picture of the overall study results that reflect the complexity and the multifaceted ontology of the phenomenon studied. RESULTS: The improvement in health workers' performance in relation to the intensity of the intervention was not linear and was characterized by improved and occasionally declining performance. Possible root causes of this performance variability included challenges in keeping knowledge and clinical skills updated, inadequate commitment of the staff to continued improvement, limited exposure to positive professional role models, poor teamwork, failure to maintain professional integrity and mal-adaptation to institutional pressures. CONCLUSION: Implementation of best-practices is a complex process that is largely unpredictable, attributed to the complexity of contextual factors operating predominantly at professional and organizational levels. There is no simple solution to implementation of best-practices. Tackling root causes of inadequate knowledge translation in this tertiary care setting will require long-term planning, with emphasis on promotion of professional ethics and values and establishing an organizational framework that enhances positive aspects of professionalism. This study has significant implications for the quality of training in medical institutions and the development of hospital leadership.