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Background: Use of antibiotics in selected cases of acute uncomplicated diverticulitis (AUD) has recently been questioned. Objective: The aim of this study is to examine the safety and efficacy of treatment regimens without antibiotics compared with that of traditional treatments with antibiotics in selected patients with AUD. Data sources: PubMed, Medline, Embase, Web of Science, and the Cochrane Library Methods: A systematic review was performed according to PRISMA and AMSTAR guidelines by searching through Medline, Embase, Web of Science, and the Cochrane Library for randomized clinical trials (RCTs) published before December 2022. The outcomes assessed were the rates of readmission, change in strategy, emergency surgery, worsening, and persistent diverticulitis. Study selection: RCTs on treating AUD without antibiotics published in English before December 2022 were included. Intervention: Treatments without antibiotics were compared with treatments with antibiotics. Main outcome measures: The outcomes assessed were the rates of readmission, change in strategy, emergency surgery, worsening, and persistent diverticulitis. Results: The search yielded 1163 studies. Four RCTs with 1809 patients were included in the review. Among these patients, 50.1% were treated conservatively without antibiotics. The meta-analysis showed no significant differences between nonantibiotic and antibiotic treatment groups with respect to rates of readmission [odds ratio (OR) = 1.39; 95% CI: 0.93-2.06; P = 0.11; I² = 0%], change in strategy (OR = 1.03; 95% CI: 0.52-2,02; P = 0.94; I² = 44%), emergency surgery (OR = 0.43; 95% CI: 0.12-1.53; P = 0.19; I² = 0%), worsening (OR = 0.91; 95% CI: 0.48-1.73; P = 0.78; I² = 0%), and persistent diverticulitis (OR = 1.54; 95% CI: 0.63-3.26; P = 0.26; I² = 0%). Limitations: Heterogeneity and a limited number of RCTs. Conclusions: Treatment for AUD without antibiotic therapy is safe and effective in selected patients. Further RTCs should confirm the present findings. [ABSTRACT FROM AUTHOR]