BACKGROUND: Abdominal pain is a common reason for children to attend the Emergency Department (ED) with acute appendicitis being the most common surgical cause. Various clinical prediction scores (CPSs) have been developed to assist in determining the risk of appendicitis; however, CPSs have been inadequately validated in children and haphazardly adopted in Australia and New Zealand (ANZ) EDs. OBJECTIVE: This study aims to compare and validate various CPSs for diagnosing pediatric appendicitis in children presenting to ANZ EDs. METHODS: This prospective multicenter observational study across 10 ANZ EDs is recruiting children 5-17 years presenting to participating EDs with acute right-sided or generalized abdominal pain lasting ≤7 days and clinician suspicion of appendicitis. CPSs will be calculated by the study team from clinician-recorded data and clinician gestalt recorded on a visual analog scale. Accuracy of CPSs will be assessed by the area under the receiver operating characteristic curve and proportions correctly identified as either low-risk or high-risk based on the CPSs published cutoffs. The final diagnosis of appendicitis will be confirmed on histopathology, and the absence of appendicitis confirmed by telephone, email, or a combination of both to follow up for those discharged directly from ED. RESULTS: This study received funding in July 2023 and started enrolment in August 2023. As of October 2024, we have enrolled and completed follow-up on 1227 participants with an expected end date in mid-2025. CONCLUSIONS: This study aims to determine the best-performing CPS for diagnosing pediatric appendicitis in ANZ EDs. Implementation of this CPS in ANZ EDs has the potential to reduce health care costs, rationalize the use of health care resources, and improve the management and outcomes of childhood appendicitis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12622001293752; https://tinyurl.com/242wwenx. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/67941.