Abstract Background To assess the cost-effectiveness of the delayed-release device of dexamethasone compared with aflibercept in the treatment of patients with naïve diabetic macular edema (DME) from a societal perspective in the healthcare sector Zaragoza III in Spain. Methods A Markov model with five states defined by visual acuity (VA) in the better-seeing eye (Snellen scale) and an additional death state were constructed. Two cohorts of patients were distributed along the VA states and treated during a year with either dexamethasone or aflibercept. One-year follow-up on each group was performed. Medical costs related to the DME treatment and follow-up, medical costs related to the DME comorbidities, and non-medical-related costs were taken into account. Costs (2020 €), health outcomes (Quality-Adjusted Life Years-QALYs), both discounted at a 3.5% annual rate, and incremental cost-effectiveness ratios (ICER: €/QALY) were determined for a lifetime horizon in the base case analysis. Results Patients treated with dexamethasone were €77,349 more costly and provided 2.667 additional QALYs (€29,002/QALY) than those treated with aflibercept. The variable efficiency per patient was calculated dividing the improvement in quality of life (on the VFQ-25 scale) by the cost of the treatment. With the obtained results it can be concluded that the efficiency of treating the patients with dexamethasone is significantly superior than the efficiency of treating them with aflibercept. Conclusions The cost per QALY gained with the delayed-release device of dexamethasone compared with the one obtained by aflibercept in the naïve DME population is just below the €30,000 threshold, below which, new drugs are sometimes regarded as cost-effective strategies in Spain. In this model, the key variables with greater impact on the cost-effectiveness results were the selected time horizon, the chosen extrapolation method and the number of aflibercept and dexamethasone injections.