IMPORTANCE: Appendicitis is the most common pediatric surgical emergency. Efforts to improve efficiency and quality of care have increased reliance on computed tomography (CT) and ultrasonography (US) in children with suspected appendicitis. OBJECTIVE: To evaluate the effectiveness of an electronic health record-linked clinical decision support intervention, AppyCDS, on diagnostic imaging, health care costs, and safety outcomes for patients with suspected appendicitis. DESIGN, SETTING, AND PARTICIPANTS: In this parallel, cluster randomized trial, 17 community-based general emergency departments (EDs) in California, Minnesota, and Wisconsin were randomized to the AppyCDS intervention group or usual care (UC) group. Patients were aged 5 to 20 years, presenting for an ED visit with right-sided or diffuse abdominal pain lasting 5 days or less. We excluded pregnant patients, those with a prior appendectomy, those with selected comorbidities, and those with traumatic injuries. The trial was conducted from October 2016 to July 2019. INTERVENTIONS: AppyCDS prompted data entry at the point of care to estimate appendicitis risk using the pediatric appendicitis risk calculator (pARC). Based on pARC estimates, AppyCDS recommended next steps in care. MAIN OUTCOMES AND MEASURES: Primary outcomes were CT, US, or any imaging (CT or US) during the index ED visit. Safety outcomes were perforations, negative appendectomies, and missed appendicitis. Costs were a secondary outcome. Ratio of ratios (RORs) for primary and safety outcomes and differences by group in cost were used to evaluate effectiveness of the clinical decision support tool. RESULTS: We enrolled 3161 patients at intervention EDs and 2779 patients at UC EDs. The mean age of patients was 11.9 (4.6) years and 2614 (44.0%) were boys or young men. RORs for CT (0.94; 95% CI, 0.75-1.19), US (0.98; 95% CI, 0.84-1.14), and any imaging (0.96; 95% CI, 0.86-1.07) did not differ by study group. In an exploratory analysis conducted in 1 health system, AppyCDS was associated with a reduction in any imaging (ROR, 0.82; 95% CI, 0.73- 0.93) for patients with pARC score of 15% or less and a reduction in CT (ROR, 0.58; 95% CI, 0.45-0.74) for patients with a pARC score of 16% to 50%. Perforations, negative appendectomies, and cases of missed appendicitis by study phase did not differ significantly by study group. Costs did not differ overall by study group. CONCLUSIONS AND RELEVANCE: In this study, AppyCDS was not associated with overall reductions in diagnostic imaging; exploratory analysis revealed more appropriate use of imaging in patients with a low pARC score. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02633735.