Background:Intussusception is the most common abdominal emergency in children. The first line treatment of uncomplicated pediatric intussusception is enema reduction. Until now, there have been no multi-center studies comparing the effectiveness and safety of UGHR and FGAR in the treatment of pediatric intussusception. The aim of this study was to compare the effectiveness and safety of the two most commonly used enema methods of pediatric intussusception: Ultrasound-guided hydrostatic reduction (UGHR) and Fluoroscopy-guided air reduction (FGAR).Methods: From November 1, 2017 to October 31, 2018, we conducted a multi-center, prospective, cohort study. Children diagnosed with intussusception in four large Children’s Medical Centers in China were divided into UGHR and FGAR groups. Stratified analysis and subgroup analysis were used for further comparison. The success and recurrence rates were used to evaluate the effectiveness of enema reduction. The perforation rate was used to evaluate the safety of enema reduction.Results: A total of 2,124 cases met the inclusion criteria (UGHR group: 1119 cases; FGAR group: 1005 cases). The success and recurrence rates in the UGHR group were higher than in the FGAR group (95.80%, 9.28% vs. 93.13%, 10.65%) (P<0.05, P>0.05), respectively. The perforation rate in the UGHR group was 0.36% compared with 0.30% in the FGAR group (P>0.05). Subgroup analysis showed the success rates in the UGHR group were higher than in the FGAR group of patients with onset time between 12h and 24h (95.56% vs 90.57%) (P<0.05). Of patients aged 4 to 24 months, the success rates in the UGHR group were also higher than in the FGAR group (95.77% vs 91.60%) (P<0.05). Stratified analysis showed the success rates in the UGHR group were higher than in the FGAR group in patients with the symptom of bloody stool (91.91% vs 85.38%) (P<0.05).Conclusions: UGHR and FGAR are safe, nonsurgical treatment methods for acute pediatric intussusception. UGHR is superior to FGAR, no radiation risk, its success rate is higher, without a difference in perforation rate, especially for patients aged 4–24 months.Level of evidence: Level II.