© The Author(s) 2022.Purpose: The study aimed to compare the anatomical and functional gains of switching to ranibizumab or aflibercept in eyes with treatment-naive diabetic macular edema (DME) which has an inadequate response to three consecutive bevacizumab injections. Methods: This observational, retrospective, comparative study presented 12-month results of 80 patients with DME. One eye of each patient was enrolled, and bevacizumab was switched as aflibercept (40 eyes) or ranibizumab (40 eyes). DME was diagnosed based on a fundoscopic examination, fundus fluorescein angiography (FFA), central macular thickness (CMT), and best-corrected visual acuity (BCVA). Results: Forty-one patients (51.2%) were male, and 39 (48.8%) were female, with a mean age of 62.3 ± 6.7 years. At the end of the study, the mean number of intravitreal injections was 8.1 ± 1.8 in the aflibercept group, whereas 8.9 ± 1.4 in the ranibizumab (p = 0.091). The mean CMT decreased from 449.2 ± 69.3 µm to 311.0 ± 48.9 µm in the aflibercept group, and from 444.9 ± 109.2 µm to 316.3 ± 54.5 µm in the ranibizumab group (for both, p < 0.0001). The mean BVCA increased from 49.2 ± 11.1 ETDRS letters to 62.5 ± 9.9 in the aflibercept group (p < 0.0001) and from 49.9 ± 12.0 ETDRS letters to 61.1 ± 9.1 in the ranibizumab group (p < 0.0001). Macular laser treatment was required in 17.5% of the aflibercept group and 22.5% of the ranibizumab group (p = 0.781). Conclusion: Significant improvement was observed with ranibizumab and aflibercept treatments in initial bevacizumab-resistant DME. Early switching therapy may contribute to better visual and anatomical outcomes.