Abstract Background: Diabetic macular edema (DME) is a common and disabling eye condition. Despite the fact that DME is a sight-threatening condition, it is also one of the most treatable. Intravitreal injection of anti-vascular endothelial growth factors (VEGFs) has emerged as the gold standard first-line treatment for DME in recent years. Aim of Study: This study compared the effects of intrav-itreal injection of ranibizumab with and without anterior chamber (AC) paracentesis. Patients and Methods: A single center comparative study enrolled 90 patients with DME. Those patients were randomly divided into two groups; 45 patients underwent intravitreal injection with ranibizumb preceded by anterior chamber paracentesis (group A). The other 45 patients underwent intravitreal injection with ranibizumb without anterior chamber paracentesis (group B). Both groups were studied preopera-tively and one day, one week, one month and three months post operatively regarding visual acuity, intraocular pressure (IOP), macular thickness and peripapillary retinal nerve fiber layer (RNFL) thickness. Results: The post-operative changes in visual acuity, central, average and peripapillary RNFL thickness was statis-tically insignificant between the two groups. However, group A (though not statistically significant) achieved higher visual acuity, lower macular thickness and better peripapillary RNFL thickness while IOP measurements were significantly higher in group B through out the follow-up period of the study. Conclusion: Both techniques gave excellent post-operative results regarding visual acuity, central and average macular thickness but those patients underwent paracentesis of AC had better peripapillary RNFL thickness and IOP.