OBJECTIVE: Optic nerve morphology is affected by genetic and acquired disease. Glaucoma is the most common optic neuropathy; autosomal-dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON) are the most prevalent hereditary optic neuropathies. These 3 entities can exhibit similar topographical changes at the optic nerve head. Both ADOA and LHON have been reported to be misdiagnosed as glaucoma. Our aim was to determine whether glaucoma subspecialists and neuro-ophthalmologists can distinguish these diagnoses on optic disc assessment alone. DESIGN: Observational study. PARTICIPANTS: Twenty-three optic nerve experts. METHODS: We randomized and masked 60 high-resolution stereoscopic optic disc photographs (15 ADOA images, 15 LHON, 15 glaucoma, and 15 normal controls). Experts were asked to assess the discs on 12 conventional topographic features and assign a presumptive diagnosis. Intra- and interanalysis was performed using the index of qualitative variation and absolute deviation. MAIN OUTCOME MEASURES: Can glaucoma specialists and neuro-ophthalmologists distinguish among the disease entities by optic nerve head phenotype. RESULTS: The correct diagnosis was identified in 85%, 75%, 27%, and 16% of the normal, glaucoma, ADOA, and LHON disc groups, respectively. The proportion of correct diagnoses within the ADOA and LHON groups was significantly lower than both normal and glaucomatous (P<0.001). Where glaucoma was chosen as the most likely diagnosis, 61% were glaucomatous, 34% were pathologic but nonglaucomatous discs, and 5% were normal. There was greater agreement for individual parameters assessed within the normal disc set when compared with pathologic discs (P<0.05). The only parameter to have a significantly greater agreement within the glaucomatous disc set when compared with ADOA or LHON disc sets was pallor, whereby experts agreed on is absence in the glaucomatous discs but were not in agreement on its presence or its absence in the ADOA and LHON discs (P<0.01). CONCLUSIONS: Optic neuropathies can result in similar topographic changes at the optic disc, particularly in late-stage disease, making it difficult to differentiate ADOA and LHON from glaucoma based on disc assessment alone. Other clinical parameters such as acuity, color vision, history of visual loss, and family history are required to make an accurate diagnosis.