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Introduction Non-operative management (NOM) of uncomplicated acute appendicitis is a well-established alternative to upfront surgery. The administration of intravenous broad-spectrum antibiotics is usually performed in hospital, and only one study described outpatient NOM. The aim of this multicentre retrospective non-inferiority study was to evaluate both safety and non-inferiority of outpatient compared to inpatient NOM in uncomplicated acute appendicitis. Methods The study included 668 consecutive patients with uncomplicated acute appendicitis. Patients were treated according to the surgeon’s preference: 364 upfront appendectomy, 157 inpatient NOM (inNOM), and 147 outpatient NOM (outNOM). The primary endpoint was the 30-day appendectomy rate, with a non-inferiority limit of 5%. Secondary endpoints were negative appendectomy rate, 30-day unplanned emergency department (ED) visits, and length of stay. Results 30-day appendectomies were 16 (10.9%) in the outNOM group and 23 (14.6%) in the inNOM group (p = 0.327). OutNOM was non-inferior to inNOM with a risk difference of—3.80% 97.5% CI (− 12.57; 4.97). No difference was found between inNOM and outNOM groups for the number of complicated appendicitis (3 vs. 5) and negative appendectomy (1 vs. 0). Twenty-six (17.7%) outNOM patients required an unplanned ED visit after a median of 1 (1–4) days. In the outNOM group, the mean cumulative in-hospital stay was 0.89 (1.94) days compared with 3.94 (2.17) days in the inNOM group (p Conclusions Outpatient NOM was non-inferior to inpatient NOM with regard to the 30-day appendectomy rate, while a shorter hospital stay was found in the outNOM group. Further, studies are required to confirm these findings.