Background Glaucoma is the leading cause of irreversible blindness worldwide. With the growing burden of glaucoma, we looked for better tools for early diagnosis and monitoring. Aim of the Work using optical coherence tomography angiography (OCTA) vessel density (VD) to document, quantify and compare microvasculature changes in macula and peripapillary region between healthy and moderate to severe primary open angle glaucoma eyes. Patients and Methods A comparative interventional prospective study was conducted on 28 eyes of 14 subjects, recruited from Ain Shams University hospitals outpatient clinic, and were subjected to imaging procedure during the period from January 2020 to May 2020. Subjects were divided into two groups: Group 1 of 14 eyes of 9 patients with moderate to severe primary open angle glaucoma (POAG), and group 2 of 14 eyes of 7 healthy sex and age-matched controls. Results a statistically significant decrease was found in VD in the peripapillary region (P < 0.001) and superficial macular regions in glaucoma subjects (P < 0.001). Conclusion OCTA proved a quantitative decrease in both peripapillary and macular vessel density as a parameter of microvascular changes associated with moderate to severe POAG. These results reflect damage to tissues relevant to the pathophysiology of POAG demonstrating OCTA importance with respect to diagnosing glaucoma and understanding the pathophysiology of this disease and, guiding future studies to evaluate more potential uses of this technology in the actual assessment of patients with glaucoma.