Objective: Prognosis of Hypoxic-Ischemic Encephalopathy (HIE) remains challenging and uncertain. This paper investigates how physicians understand and address the ethical challenges of prognostic uncertainty in the case of neonatal HIE, contextualized within the social science literature. Study design: Semi-structured interviews were conducted with 12 Canadian neurologists and neonatologists, addressing their perspectives and clinical experiences concerning neonatal HIE prognostication. Interviews were analyzed using thematic content analysis. Results: Participants unanimously recognized uncertainty in their prognostication. They identified several sources contributing to uncertainty in HIE prognostication, including etiology and underlying pathophysiologic mechanisms, statistical limitations, variable clinical data, the dynamic process of neurodevelopment, or the impact of hypothermia treatment. Unlike in some other literature, some physicians in this study talked about ways to render uncertainty explicit rather than hide it. Conclusion: Results from this study support the call for recognition of the ubiquitous uncertainty surrounding this act in medical education and training.