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We combined them to investigate why patients with optic neuritis (ON) exhibit a wide variation in severity of acute visual loss, with the following objectives: (1) To determine how structural and electrophysiological changes in the anterior and posterior visual pathways contribute to acute visual loss. (2) To combine these data with fMRI, to investigate whether cortical activity modulates visual acuity. The visual system of 28 patients with acute unilateral ON was assessed. Linear regression modeling was used to identify parameters associated with acute visual loss, and to determine whether fMRI activity was associated with vision, after accounting for structural and electrophysiological predictors, age, and gender. Optic nerve lesion length and visual evoked potential (VEP) amplitude were associated with visual loss. Bilateral activation in the extra\u2010striate occipital cortex correlated directly with vision, after adjusting for optic nerve lesion length, VEP amplitude, and demographic characteristics. These data suggest that acute visual loss is associated with the extent of inflammation and conduction block in the optic nerve, but not with pathology in the optic radiations or occipital cortex. The association of better vision with greater fMRI responses, after accounting for factors which reduce afferent input, suggests a role for adaptive neuroplasticity within the association cortex of the dorsal stream of higher visual processing. Longitudinal studies will clarify whether different extra\u2010striate cortical regions play a role in adaptive plasticity in the acute and chronic stages of injury. 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