Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are marked by inflammatory demyelinating lesions throughout the central nervous system, including optic nerve. Neuronal loss also occurs in MS and EAE lesions, but it is not known whether neuronal loss occurs secondary to inflammation, or as a primary process. In the current study, the relationship of inflammation to retinal ganglion cell (RGC) loss during acute optic neuritis is examined. RGCs were labelled with Flourogold, and EAE was induced in SJL/J mice by immunization with proteolipid protein peptide 139-151 (PLP). At various time points, RGCs were counted and optic nerves were examined for inflammatory cell infiltrates. No optic neuritis was detected prior to day 9 following immunization. Incidence of optic neuritis was 30% at day 9 and increased to over 70% by day 11, remaining high through day 18. In contrast, no RGC loss was detected in eyes with optic neuritis until day 14. A 43.1% reduction in RGC numbers at day 14 increased to 50.8% by day 18. No RGC loss occurred in eyes without optic neuritis. The fact that inflammation precedes RGC loss suggests that neuronal loss during optic neuritis occurs secondary to the inflammatory process. © 2006 SAGE Publications.