BACKGROUND AND OBJECTIVES: Acute severe neurologic involvement is the most threatening complication in children with hemolytic-uremic syndrome (HUS). Our primary study objectives were to describe the association between acute neurologic manifestations (ANMs) and in-hospital mortality among children with HUS. METHODS: Using the Pediatric Health Information System database, in this retrospective multicenter cohort study, we identified the first HUS-related inpatient visit among children ≤18 years (years 2004–2018). Frequency of selected ANMs and combinations of ANMs, as well as the rate of mortality, was calculated. Multivariate logistic regression was used to identify the association of ANMs and the risk of in-hospital mortality.