PURPOSE: To calculate costs required to prevent center-involved diabetic macular edema (CI-DME) or proliferative diabetic retinopathy (PDR), and to improve the diabetic retinopathy severity score (DRSS) with intravitreal anti-VEGF injections, as reported for aflibercept in 2 randomized control trials. DESIGN: Cost-effectiveness analysis modeling based on published data. SUBJECTS: None. METHODS: Results from PANORAMA and the Diabetic Retinopathy Clinical Research Network Protocol W were analyzed. Parameters collected included DRSS, risk reduction of PDR, risk reduction of CI-DME, and the number of treatments required. Costs were modeled based on 2020 Medicare reimbursement data practice settings of hospital-based facility and nonfacility. MAIN OUTCOME MEASURES: Cost to prevent cases of PDR and CI-DME and to improve DRSS stage. RESULTS: Over 2 years in Protocol W, the cost required to prevent 1 case of PDR was $83 000 ($72 400) in the facility (nonfacility) setting; in PANORAMA, the corresponding 2-year costs were $89 400 ($75 000) for the 2-mg aflibercept every 16 weeks (2Q16) arm, and $91 200 ($89 900) for the 2-mg aflibercept every 8 weeks as needed (2Q8PRN) arm. To prevent 1 case of CI-DME with vision loss in Protocol W, the cost was $154 000 ($133 000). For all CI-DME, with and without vision loss, in PANORAMA, the costs to prevent a case were $70 900 ($59 500) for the 2Q16 arm and $90 000 ($88 800) for the 2Q8PRN arm. In Protocol W, the overall accumulated total for cost/DRSS unit change at the 2-year point for facility (nonfacility) setting was $2700 ($2400)/DRSS. In the first year alone, it was $2100 ($1800)/DRSS and in the second year, it was $6100 ($5300)/DRSS. CONCLUSIONS: There is a considerable cost associated with the prevention of PDR and CI-DME with intravitreal aflibercept injections. A price per unit of change in DRSS is a new parameter that might serve as a benchmark in future utility analyses that could be used to bring the perspective to cost-utility considerations.