Alternative causes of optic neuritis (ON), other than primary demyelination or non-demyelinating optic neuropathies which can mimic acute ON, should be rigorously considered if a patient with presumed ON does not follow the typical clinical course or has a normally appearing brain on magnetic resonance imaging. A thorough differential diagnosis includes viral and bacterial optic neuropathies, ischemic optic neuropathies, Devic's neuromyelitis optica, compressive or infiltrative optic neuropathies, Leber's hereditary optic neuropathy and toxic and deficiency optic neuropathies. All patients should undergo a complete neuroophthalmological examination to help exclude other diseases mimicking ON. Atypical clinical cases of optic neuropathy require further specific laboratory, neurophysiological and imaging tests to make a correct and early diagnosis.