Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is accepted as the gold standard treatment for center-involving diabetic macular edema (CI-DME). Adjunctive administration of topical dorzolamide may enhance the therapeutic effects of anti-VEGF agents. In this study, we compared the efficacy of topical dorzolamide plus intravitreal injection of bevacizumab (IVB) versus IVB alone in patients with bilateral DME. This prospective, randomized contralateral eye study was carried out in a tertiary referral ophthalmology center, Al-Zahra Eye Hospital, Zahedan, Iran, between April 2021 and April 2022. Thisstudy included 50 eyes of 25 patients with bilateral DME. All eyes received three consecutive monthly injections of IVB. For each patient, one eye was randomized to instill dorzolamide eye drops three times a day as an intervention, and the other received artificial tear drops as a placebo. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) were evaluated before starting treatment and then monthly for the first three months. Among 25 included patients, the average age was 56.64 ± 7.97 years, and 48% were female. BCVA did not improve significantly in any groups (P > 0.05). No significant difference was observed in terms of BCVA between the intervention and control groups (P > 0.05). The present study showed a decrease in CMT in both study groups (P < 0.05). At month 3, the decrease in mean CMT from baseline was significantly higher in eyes receiving topical dorzolamide compared to the control group (-88.92 ± 82.90 vs. -37.64 ± 86.16 µM, respectively; P = 0.037). IOP decreased significantly only in eyes receiving dorzolamide (P < 0.001). The results of the present study indicate that adjunctive administration of topical dorzolamide has a beneficial effect on CMT reduction from baseline, but it did not have an additive effect on BCVA improvement compared to IVB monotherapy.