AIM: To compare the damage pattern of the peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell-inner plexiform layer (mGCIPL) between early glaucomatous and non-glaucomatous optic neuropathy (EGON and NGON). METHODS: It is a cross-sectional study. Thirty-eight healthy controls, 74 EGONs and 70 NGONs with comparable average pRNFL loss were included. The NGON group included 23 eyes of optic neuritis (ON), 13 eyes of hereditary optic neuropathy (HON), 19 eyes of toxic optic neuropathy (TON) and 15 eyes of compressive neuropathy (CON). The sectoral pRNFL and mGCIPL thickness obtained by high definition optical coherence tomography were analyzed. RESULTS: Compared to normal controls, the pRNFL thickness in all quadrants showed a decrease in both EGON and NGON group (P<0.001), but the average pRNFL thickness of EGON group was not different to that of NGON group (P=0.94). The inferior and superior pRNFL was thinner in EGON group compared to NGON group (P<0.001). The temporal pRNFL was thinner in NGON group compared to EGON group (P<0.001). No statistically significant difference was found in nasal pRNFL between EGON and NGON. While the nasal pRNFL was thinner in CON than other three types of NGON (P=0.01), no statistically significant difference was found in other three quadrantal pRNFL among the four types of NGON (P>0.05). The mGCIPL of EGON and NGON group were thinner than control group (P<0.001). In EGON group the severest sites of mGCIPL reduction was located at inferotemporal and inferior sectors. While, compared to EGON group, the average mGCIPL of NGON group were significantly thinner, especially in superonasal and inferonasal sectors (P<0.001). CONCLUSION: The damage pattern of pRNFL and mGCIPL caused by glaucoma is distinct from other NGON such as ON, TON, HON and CON, and this characteristic damage pattern is helpful in differentiating early glaucoma from other NGON.