AIM: To assess the differences in average and sectoral peripapillary retinal nerve fiber layer (pRNFL) thickness using spectral domain optical coherence tomography (SD-OCT) in patients with non-arteritic anterior ischemic neuropathy (NAION) compared with those with primary open angle glaucoma (POAG). METHODS: A comprehensive literature search of the PubMed, Cochrane Library, and Embase databases were performed prior to October, 2021. Studies that compared the pRNFL thickness in NAION eyes with that in POAG eyes with matched mean deviation of the visual fields were included. The weighted mean difference (WMD) with 95% confidence interval (CI) was used to pool continuous outcomes. RESULTS: Ten cross-sectional studies (11 datasets) comprising a total of 625 eyes (278 NAION eyes, 347 POAG eyes) were included in the qualitative and quantitative analyses. The pooled results demonstrated that the superior pRNFL was significantly thinner in NAION eyes than in POAG eyes (WMD=-6.40, 95%CI: -12.22 to -0.58, P=0.031), whereas the inferior pRNFL was significant thinner in POAG eyes than in NAION eyes (WMD=11.10, 95%CI: 7.06 to 15.14, P≤0.001). No difference was noted concerning the average, nasal, and temporal pRNFL thickness (average: WMD=1.45, 95%CI: -0.75 to 3.66, P=0.196; nasal: WMD= -2.12, 95%CI: -4.43 to 0.19, P=0.072; temporal: WMD= -1.24, 95%CI: -3.96 to 1.47, P=0.370). CONCLUSION: SD-OCT based evaluation of inferior and superior pRNFL thickness can be potentially utilized to differentiate NAION from POAG, and help to understand the different pathophysiological mechanisms between these two diseases. Further longitudinal studies and studies using eight-quadrant or clock-hour classification method are required to validate the obtained findings.