Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been found efficacious in the treatment of type 2 diabetes (T2D), demonstrating the ability to lower HbA1c, and having the potential for inducing weight loss and reducing the risk of hypoglycemia, compared with other antihyperglycemic agents. Currently, 4 once-weekly (OW) GLP-1 RAs are approved: albiglutide, dulaglutide, exenatide ER, and recently, semaglutide. This review compares the relative safety of OW GLP-1 RAs, as well as their safety in comparison to other antihyperglycemic agents, using safety data reported in key sponsor-led phase 3 studies of the 4 OW GLP-1 RAs. The favorable safety profiles of OW GLP-1 RAs, added to their efficacy and the favorable weekly dosing regimen, make these agents appropriate options for patients with T2D. However, there are key differences within this class of drugs in macrovascular, microvascular, gastrointestinal and injection-site reaction adverse events, and these should be considered when healthcare providers are prescribing therapy.