BackgroundMounting evidence suggests that breast reduction surgery displays higher rates of surgical site infections (SSI) than initially presumed. Objective of this network meta-analysis is to evaluate the effectiveness of different antibiotic regimens in the prophylaxis from surgical site infections and delayed wound healing (DWH) following breast reduction.MethodsA network meta-analysis was conducted using a predetermined protocol after searching the electronic databases MEDLINE, Scopus, the Cochrane Library and US National Institutes of Health Ongoing Trials Register from inception to July 2022. The included studies had to examine breast reduction in females with at least 1-month follow-up, receiving antibiotics in an intervention arm compared to a control arm. The quality of studies was assessed using the Cochrane risk of bias tool. A frequentist Mantel-Haenszel approach was adopted for the reported SSI rates while an inverse variance random effects model was used for the DWH rates.ResultsA total of 10 studies was included in the analysis involving 1331 patients. All but one study controlled for major risk factors, and no differences were observed in patients’ baseline characteristics. Antibiotic administration significantly reduced the SSI rate after breast reduction, with the prolonged antibiotic regimen being the most efficacious (odds ratio [OR]: 0.36 [95%CI: 0.15–0.85]). No statistically significant reduction in delayed wound healing rate was revealed among the regimens.ConclusionsAntibiotics mitigate the SSI rate after breast reduction. This meta-analysis provides an evidence-based strategy to optimize antibiotic administration. Further research is needed though to examine antibiotic prophylaxis on delayed wound healing.Level of Evidence IIIThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authorswww.springer.com/00266.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00266-023-03313-2.