TOPIC: Diabetic macular edema (DME) can be treated with either intravitreal anti-VEGF injections or intravitreal corticosteroid injections. CLINICAL RELEVANCE: We provide an updated meta-analysis of the comparative efficacy and safety of intravitreal steroids and anti-VEGF agents for DME. METHODS: A systematic search was performed on Ovid MEDLINE, Embase, and Cochrane Controlled Register of Trials from January 2005 to November 2021. Inclusion criteria included published randomized clinical trial data comparing the efficacy and safety of intravitreal steroids versus anti-VEGF agents for DME. Nonrandomized, noncomparative, and non-English studies were excluded. RESULTS: Fourteen randomized clinical trials reporting on 827 eyes were included. Between these 2 treatments, our analysis revealed no significant difference in best-corrected visual acuity (BCVA) outcomes at 3 months (P = 0.11), 6 months (P = 0.21), 12 months (P = 0.24), and final follow-up (P = 0.91). Retinal thickness was significantly lower with steroid treatment at 3 months (P = 0.04), 6 months (P < 0.00001), and final follow-up (weighted mean difference = 39.99 µm; 95% confidence interval [CI] = 14.58,65.41; P = 0.002); however, there was no significant difference at 12 months (P = 0.18). Intravitreal anti-VEGF agents were associated with a lower incidence of intraocular pressure-related adverse events (risk ratio = 0.13; 95% CI = 0.05, 0.34; P < 0.00001). There was no significant difference between comparators for other adverse events, including cataract-related adverse events (P = 0.22). CONCLUSIONS: Overall, intravitreal steroid treatment for DME was associated with no significant differences in BCVA, a significantly lower retinal thickness, and a higher risk of intraocular pressure-related events. The certainty of evidence ranged from low to moderate and the analysis was limited by heterogeneity. Our results reinforce the importance of a continual reevaluation of the role of intravitreal steroids in DME management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.