: To report on the outcome of intravitreal brolucizumab compared to aflibercept in patients with diabetic macular edema (DME). : Prospective, observational, study in 35 eyes of 24 patients with a loading dose of five injections of 6 mg brolucizumab every 6 weeks (q6w, treatment-naïve eyes) or a minimum of two injections of brolucizumab q6w after the switch (recalcitrant DME eyes), followed by a treat and extend (T&E) regimen. The results were compared with 40 eyes of 31 DME patients who were treated with aflibercept. The data were obtained from the Berlin Macula Registry. The primary outcome measure was the change in best-corrected visual acuity (BCVA) at week 36. Secondary outcome measures were the change in central retinal thickness (CRT) and the treatment intervals until week 36. : BCVA increased significantly in treatment-naïve DME eyes treated with either brolucizumab (+0.12 logMAR, +6.4 letters, = 0.03) or aflibercept (+0.19 logMAR, +9.5 letters, = 0.001). In recalcitrant DME eyes, BCVA also increased significantly after switching to brolucizumab (+0.1 logMAR, +5 letters, = 0.006) or aflibercept (+0.11 logMAR, +5.5 letters, = 0.02). All treatment-naïve and recalcitrant DME eyes had a significant decrease in CRT after treatment with brolucizumab ( = 0.001 and < 0.001) or aflibercept ( = 0.0002 and = 0.03). At week 36, the mean treatment interval for brolucizumab was 11.3 weeks, while for aflibercept, it was 6.5 weeks for treatment-naïve eyes and 9.3 weeks vs. 5.3 weeks for pretreated eyes. : In routine clinical practice, patients with treatment-naïve and recalcitrant DME showed a favorable response to brolucizumab and aflibercept therapy, with a reduced injection frequency after brolucizumab treatment.