Purpose To evaluate the efficacy of topical α-2 agonist (brimonidine) in the treatment of mixed diabetic maculopathy (with edema and ischemia). Design This is a prospective randomized case series. Patients and methods Thirty eyes of 30 patients were included in this study. All eyes had mixed diabetic maculopathy as diagnosed by fluorescein angiography and spectral domain optical coherence tomography. The cases were divided into two groups: group I (15 eyes) was treated by intravitreal triamcinolone injection and topical brimonidine twice daily for 3 months, and group II (15 eyes) was treated only by intravitreal triamcinolone injection. Visual acuity, fluorescein angiography, and optical coherence tomography were done for all patients before the beginning of the treatment and everymonth for 3 months to detect the changes in logarithm of minimal angle of resolution (logMAR) visual acuity and the changes in the size of the foveal avascular zone and macular thickness. Results The mean logMAR visual acuity improved from 0.9±0.012 to 0.4±0.1 in group I and from 0.8±0.1 to 0.5±0.02 in group II after 3 months of treatment, with a statistically significant difference between the two groups (P=0.01). The mean central macular thickness improved from 475±25 to 395±11 μm in group I and from 480±14 to 387± 9 μm in group II after 3 months of treatment, with no statistically significant difference between the two groups (P=0.5). There was more improvement in the size of the foveal avascular zone with fewer disturbances of its edges in group I when compared with group II throughout the follow-up period. The mean intraocular pressure after 3 months of treatment was 11.5±0.1mmHg in group I and 18.5±0.02mmHg in group II, with a significant difference between the two groups (P=0.01). Conclusion α-2 Agonist (brimonidine) has a role in the treatment of mixed diabetic maculopathy.