Abstract Background: Risk of cancer is a major concern in the development of drugs for the treatment of obesity and diabetes. In randomized controlled trials (RCTs) of the liraglutide development program, a glucagon-like peptide-1 receptor agonist (GLP-1RA), subjects treated with the active drug had a higher absolute number of breast cancer events. Aim: To assess whether patients treated with GLP-1RAs had a higher risk of breast neoplasms. Methods: We searched MEDLINE, Embase, Web of Science, and CENTRAL from inception to February 8, 2020. Three pairs of reviewers examined and retrieved abstractsand full-text articles for RCTs of GLP-1RAs versus non-GLP-1RA controls(active or placebo) in adults with overweight, obesity, prediabetes, or diabetes,with a minimum follow-up period of 24 weeks and which reported at least oneevent of breast cancer or benign breast neoplasm. Divergences were dealt withby consensus. Researchers extracted study-level data and assessed within-study risk of bias with the RoB 2.0 tool and quality of evidence with GRADE. This study follows PRISMA reporting guidelines. Results: We included 52 trials, of which 50 reported breast cancer events and 11 reported benign breast neoplasms. Overall methodological quality was high. Among 48267 subjects treated with GLP-1RAs, 130 developed breast cancer compared to 107 of 40755 controls (relative risk [RR], 0.98; 95% confidence interval [CI], 0.76 to 1.26). Subset analyses according to follow-up, participant/investigator blinding, and type of GLP-1RA did not reveal any differences. The risk of benign breast neoplasms also did not differ between groups (RR, 0.99; 95% CI, 0.48 to 2.01). Trial sequential analysis provided evidence that the sample size was sufficient to avoid missing alternative results. Conclusion: Treatment with GLP-1RAs for obesity and diabetes does not increase the risk of breast neoplasms. Register: This systematic review was preregistered in PROSPERO (CRD42019132704).