Our retrospective, single-center, observational study aimed to evaluate the initial responses to intravitreal injection of brolucizumab (IVBr) in patients undergoing anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). In total, 23 eyes of 20 patients with DME treated with at least one intravitreal injection of ranibizumab or aflibercept within one year and then switched to IVBr were included. Best corrected visual acuity (BCVA), central macular thickness (CMT), and macular volume (MV) on optical coherence tomography images were evaluated just before the most recent conventional anti-VEGF (ranibizumab/aflibercept) injection therapy (V1), one month after the most recent traditional anti-VEGF therapy (V2), just before the first IVBr (V3), and one month after the first IVBr (V4). BCVA, CMT, MV, and presence of intraocular inflammation (IOI) were evaluated at each visit. Anterior chamber flare values were also examined at V3 and V4. BCVA showed significant improvement at V2 (0.30 ± 0.23) than V1 (0.39 ± 0.29) and at V4 (0.34 ± 0.26) than V3 (0.48 ± 0.34) (P= 0.002,P< 0.001). However, no significant difference was observed between V2 and V4 (P= 0.257). CMT was significantly thinner at V2 (346.8 ± 90.2 µm) than V1 (495.5 ± 123.8 µm), and at V4 (322.2 ± 95.7 µm) than V3 (536.5 ± 166.0 µm) (P< 0.001,P< 0.001), but no significant difference was observed between V2 and V4 (P= 0.140). MV was significantly smaller at V2 (11.6 ± 2.0 mm3) than V1 (12.6 ± 1.9 mm3) and at V4 (11.2 ± 2.0 mm3) than V3 (12.6 ± 2.0 mm3) (P< 0.001,P< 0.001), and even significantly smaller at V4 than V2 (P= 0.009). No patient had IOI. No significant changes were observed in anterior chamber flare values between V3 and V4 (25.6 ± 14.6 vs. 24.0 ± 11.5 photon count/ms;P= 0.543). Both CMT and MV significantly reduced without any adverse events one month after switching from conventional anti-VEGF to IVBr therapy for DME, including IOI. MV was significantly lower for IVBr than anti-VEGF therapy after one month of treatment. Therefore, brolucizumab may be a viable treatment option for DME patients considering switching from conventional anti-VEGF agents for various reasons, such as poor response or inability to extend dosing intervals.