PURPOSE: To calculate costs of treatment for diabetic macular edema (CI-DME) with bevacizumab-first (step therapy) compared to aflibercept monotherapy. DESIGN: Cost analysis of treatment arms based on a published study SUBJECTS: None METHODS: Published results from the Diabetic Retinopathy Clinical Research Network (DRCR.net) protocol AC were used to assess costs. Data incorporated in a usage and outcome model included frequency of injections, medication type, visits, and imaging. Costs were modeled based on 2022 Medicare reimbursement data for both facility (hospital-based) and non-facility settings in Miami. Outcomes were similar in Protocol AC so were not differentially studied. Results were extrapolated so as to estimate lifetime (17 years for the age of the cohort). RESULTS: Over the 2 years reported in protocol AC, the cost required to treat in the facility (nonfacility setting) was $42,000 ($32,000) in the aflibercept monotherapy group and $29,000 ($22,000) in the bevacizumab-first group. Extrapolated modeled lifetime costs were $158,000 ($136,000) and $125,000 ($103,000), respectively. The total cost with bevacizumab-first was 33% lower at year 2 and 21% lower at year 17 compared with aflibercept monotherapy. Savings per year for the 2 year results were $6,500 ($5000) in the facility (non-facility) setting. For the extrapolated 17 year model annual savings were $1900 ($1900) in the facility (non-facility) setting. The professional fees accounted for a minority of overall costs; in contrast, medication costs accounted for 82% of the total costs for the aflibercept monotherapy and 73% in the bevacizumab-first group at 2 years. Our model predicted an additional 15% lifetime cumulative savings if patients still not meeting threshold criteria after switching to aflibercept were placed back on bevacizumab, and a similar degree of improvement if those on not meeting threshold criteria on aflibercept monotherapy were switched to bevacizumab. MAIN OUTCOME MEASURES: Cost of treatment options. CONCLUSION: Medication is the dominant driver of the total expenses associated with the treatment of diabetic macular edema. While cost savings are realized with bevacizumab-first step therapy, the magnitude was not as much as might be intuited, probably due to the high (70%) incidence of patients switching to aflibercept within Protocol AC.