OBJECTIVE: Anti-vascular endothelial growth factor therapies have revolutionized the treatment of clinically significant diabetic macular edema (CSDME); yet these agents are expensive, and whether they are cost-effective is unclear. The purpose of this study is to determine the most cost-effective treatment option for patients with newly diagnosed CSDME: focal laser photocoagulation alone (L), focal laser plus intravitreal ranibizumab (L+R), focal laser plus intravitreal bevacizumab (L+B), or focal laser plus intravitreal triamcinolone (L+T) injections. DESIGN: Cost-effectiveness analysis. PARTICIPANTS: Hypothetical cohort of 57-year-old patients with newly diagnosed CSDME. METHODS: By using a Markov model with a 25-year time horizon, we compared the incremental cost-effectiveness of treating patients with newly diagnosed CSDME using L, L+R, L+B, or L+T. Data came from the DRCRnet randomized controlled trial, the Medicare fee schedule, and the medical literature. MAIN OUTCOME MEASURES: Costs, quality-adjusted life years (QALYs), and incremental costs per QALY gained. RESULTS: Compared with L, the incremental cost-effectiveness of L+R and L+B was $89 903/QALY and $11 138/QALY, respectively. L+T was dominated by L. A probabilistic sensitivity analysis demonstrated that, at a willingness to pay (WTP) of $50 000/QALY, L was approximately 70% likely to be the preferred therapy over L+R and L+T. However, at a WTP of $100 000/QALY, more than 90% of the time, L+R therapy was the preferred therapy compared with L and L+T. In the probabilistic sensitivity analysis, L+B was found to be the preferred therapy over L and L+T for any WTP value >$10 000/QALY. Sensitivity analyses revealed that the annual risk of cerebrovascular accident would have to be at least 1.5% higher with L+B than with L+R for L+R to be the preferred treatment. In another sensitivity analysis, if patients require <8 injections per year over the remainder of the 25-year time horizon, L+B would cost <$100 000/QALY, whereas L+R would be cost-effective at a WTP of $100 000/QALY if patients require fewer than 0.45 injections per year after year 2. CONCLUSION: With bevacizumab and ranibizumab assumed to have equivalent effectiveness and similar safety profiles when used in the management of CSDME, bevacizumab therapy confers the greatest value among the different treatment options for CSDME. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.