Background: Urinary tract infection (UTI) is common in children. Differentiating lower UTI from acute pyelonephritis (APN) is of great importance in children since early diagnosis and timely management can prevent kidney scarring and associated complications. Objectives: We aimed to compare the diagnostic performance of serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood cell (WBC) count with interleukin-6 (IL-6) for the diagnosis of APN in children. Methods: This cross-sectional study included 38 children with APN (based on clinical findings and positive urine culture) aged 1 month to 15 years admitted to Bandar Abbas Pediatric Hospital, Bandar Abbas, Iran, during 2019-2020. Serum CRP, WBC, IL-6, and WBC count were measured in all children. Age and sex of the participants were also recorded. Results: The mean ± SD age of the children was 65.82±46.67 months, of whom 23 (60.5%) were girls. The sensitivity of WBC, ESR, CRP, and IL-6 for the early diagnosis of APN was 39.5%, 71.1%, 60.5%, and 71.1%, respectively. Taking the results of ESR, CRP, and WBC into account as the basis of diagnosis, altogether 9.98 pg/mL was the best cut-off of serum IL-6 for the diagnosis of APN with 70%-80% sensitivity and 56.5%-73.7% specificity. A significant correlation was found between serum IL-6 and CRP, ESR, and WBC with the strongest correlation between IL-6 and CRP (r=0.451, P=0.004). Age and sex did not affect these correlations. The sensitivity of serum IL-6 at the 5 pg/mL cut-off for the diagnosis of APN was higher in boys and children younger than 6 years. Conclusion: IL-6 can diagnose APN in children aged 1 month to 15 years with 71.1% sensitivity. Its sensitivity is superior to CRP and WBC and comparable with ESR in this regard.