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The use of a single C-reactive protein (CRP) value to differentiate between bacterial and non-bacterial causes is limited. Estimated CRP velocity (eCRPv) has shown promise in enhancing such discrimination in adults. This study aims to investigate the association between eCRPv and bacterial etiologies among pediatric patients with very elevated CRP levels. We conducted a retrospective analysis of patients under 18 years of age who had been admitted to our Pediatric Emergency Department from 2018 to 2020 with a fever and CRP levels ≥ 150 mg/L. Bacterial and non-bacterial etiologies were determined from hospital discharge diagnoses, which were monitored independently by three physicians from the research team. The records of 495 suitable patients (51.2% males, median age 3.2 years) were retrieved of whom 444 (89.7%) were eventually diagnosed with bacterial infections. The mean CRP levels were significantly higher for bacterial etiologies compared with other causes (209.2 ± 59.8 mg/L vs. 185.6 ± 35.8 mg/L, respectively, p < .001), while the mean eCRPv values did not differ significantly (p = .15). In a time course analysis, we found that specifically in patients presenting ≥ 72 h after symptom onset, only a eCRPv1 level > 1.08 mg/L/h was an independent predictor of bacterial infection (aOR = 5.5 [95% CI 1.7-17.8], p = .004).   Conclusion: Pediatric patients with very high CRP levels and fever mostly have bacterial infections. eCRPv levels, unlike CRP values alone, can serve as the sole independent predictor of bacterial infection > 72 h from symptom onset, warranting further prospective investigations into CRP kinetics in pediatric patients. What is Known: • The use of a single C-reactive protein (CRP) value to differentiate between bacterial and non-bacterial causes is limited. • Estimated CRP velocity (eCRPv) has shown promise in enhancing such discrimination in adults, but data on CRP kinetics in pediatric patients is sparse. What is New: • eCRPv levels, unlike CRP values alone, can serve as the sole independent predictor of bacterial infection > 72 h from symptom onset in pediatric patients with remarkably elevated CRP levels., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)