This is a cross sectional study comparing the retinal features of optic neuritis (ON) between 20 multiple sclerosis (MS) and 16 neuromyelitis optica (NMO) patients with a history of ON (visual acuity at time of attack > 20/100) matched for age and gender using optical coherence tomography (OCT) and fundoscopy. Compared to MS, NMO patients often have: 1) vascular changes including attenuation of the peripapillary vascular tree (3/40 MS eyes, 22/32 NMO eyes, P=0.001), and focal arteriolar narrowing (0/40 MS eyes and 9/32 NMO eyes, P<0.0001), 2) a lower average nerve fiber layer (NFL) thickness (59.2 um compared to 82.0 um in MS, P=0.004) and 3) nearly twice the NFL thinning after controlling for final visual acuity (32.1 versus 17.6 um, P=0.004). Patients with NMO have more severe and diffuse axonal injury of the NFL compared to MS. These NFL and fundoscopic findings suggest that some of the injury seen in NMO may be vascularly mediated. These inner retinal vascular changes are reminiscent of blood vessel wall thickening previously reported in the optic nerve and spinal cord (SC) at autopsy. If the retinal changes share a common pathology to those in the SC and optic nerve these observations suggest that vascular changes may be detectable during life.