Background: The contralateral effect of intravitreal Anti-Vascular Endothelial Growth Factor (anti- VEGF) on the fellow eye is still controversial. Objectives: The aim of the current work was to evaluate the contralateral effect of anti-VEGF injection on the fellow eye in patients with bilateral diabetic macular edema (DME). Patients and Methods: This prospective interventional study included a total of 30 female patients with bilateral DME aged from 30 to 70 years, attending at Department of Ophthalmology, International Medical Center, Armed Forces. This study was conducted to assess the effect of unilateral intravitreal injection of anti-VEGF on the fellow eye. It was conducted between 2018 to 2019. Results: The mean age ± SD was 61.0 ± 7.8 years and duration of DM was 17.50 ± 9.797 years. All patients were obese with mean body mass index (BMI) 37.3 ± 3.5. 21 cases were hypertensive, 2 patients had albuminuria. Statistically significant decrease in central retinal thickness (CRT) in both eyes were found with mean ± SD reduction 83.07 ± 31.67 µm in injected eye and 11.30 ± 12.78 µm in the untreated eye from baseline, no significant improvement in best corrected visual acuity (BCVA). There was no significance correlation between hypertension and improvement in CRT, while the patients with albuminuria showed worsening in CRT in untreated eye. Conclusion: It could be concluded that ranibizumab can escape into the systemic circulation and reduce contralateral CRT and the systemic condition could affect the outcome of the treatment.