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Background Shiga toxin–producing Escherichia coli (STEC) infections are leading causes of pediatric acute renal failure. Identifying hemolytic uremic syndrome (HUS) risk factors is needed to guide care. Methods We conducted a multicenter, historical cohort study to identify features associated with development of HUS (primary outcome) and need for renal replacement therapy (RRT) (secondary outcome) in STEC-infected children without HUS at initial presentation. Children aged <18 years who submitted STEC-positive specimens between January 2011 and December 2015 at a participating study institution were eligible. Results Of 927 STEC-infected children, 41 (4.4%) had HUS at presentation; of the remaining 886, 126 (14.2%) developed HUS. Predictors (all shown as odds ratio [OR] with 95% confidence interval [CI]) of HUS included younger age (0.77 [.69–.85] per year), leukocyte count ≥13.0 × 103/μL (2.54 [1.42–4.54]), higher hematocrit (1.83 [1.21–2.77] per 5% increase) and serum creatinine (10.82 [1.49–78.69] per 1 mg/dL increase), platelet count <250 × 103/μL (1.92 [1.02–3.60]), lower serum sodium (1.12 [1.02–1.23 per 1 mmol/L decrease), and intravenous fluid administration initiated ≥4 days following diarrhea onset (2.50 [1.14–5.46]). A longer interval from diarrhea onset to index visit was associated with reduced HUS risk (OR, 0.70 [95% CI,.54–.90]). RRT predictors (all shown as OR [95% CI]) included female sex (2.27 [1.14–4.50]), younger age (0.83 [.74–.92] per year), lower serum sodium (1.15 [1.04–1.27] per mmol/L decrease), higher leukocyte count ≥13.0 × 103/μL (2.35 [1.17–4.72]) and creatinine (7.75 [1.20–50.16] per 1 mg/dL increase) concentrations, and initial intravenous fluid administration ≥4 days following diarrhea onset (2.71 [1.18–6.21]). Conclusions The complex nature of STEC infection renders predicting its course a challenge. Risk factors we identified highlight the importance of avoiding dehydration and performing close clinical and laboratory monitoring. [ABSTRACT FROM AUTHOR]