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We developed a protocol to identify candidates for non-operative management (NOM) of uncomplicated appendicitis. Our objective was to evaluate protocol efficacy with the null hypothesis that clinical outcomes, hospital readmission rates, and hospital charges would be unchanged after protocol implementation.We performed a single-center 4-year propensity score matched retrospective cohort analysis of 406 patients with acute uncomplicated appendicitis. The protocol recommended NOM for patients with modified Alvarado score ≤6 and no appendicolith. Patients admitted before (n = 203) and after (n = 203) protocol implementation were matched by Charlson comorbidity index, duration of symptoms, and modified Alvarado score. Outcomes included operative management, days on antibiotic therapy, length of stay, and hospital charges, as well as readmissions, complications, and mortality within 180 days.Baseline characteristics were similar between groups (age 31 years, ASA class 2.0, Charlson comorbidity index 0.0). Protocol compliance was higher when the protocol recommended appendectomy (97%) rather than NOM (73%, p < 0.001). The incidence of operative management decreased from 99% to 82% after protocol implementation (p < 0.001). In the protocol group, there was a lower incidence of open surgery (4% vs. 10%, p = 0.044) despite a longer interval between admission and surgery (8.6 vs. 7.1 hours, p < 0.001). After protocol implementation, 51 patients had NOM: 18 failed NOM during admission and 6 failed NOM after discharge. Compared to the pre-protocol group, the protocol group had similar length of stay, antibiotic days, and overall complication rates, but more readmissions (6% vs. 1%, p = 0.019) and lower hospital charges for the index admission ($5,630 vs. $6,878, p < 0.001).Implementation of a protocol to identify candidates for NOM of acute uncomplicated appendicitis was associated with lower rates of open surgery, fewer appendectomies, decreased hospital charges, and no difference in overall complications despite high rates of readmission and failure of NOM.Therapeutic study, level IV.