Neuromyelitis optica is a distinct CNS demyelinating disease associated with the autoantibody NMO-IgG, which targets the water channel aquaporin-4. Neuromyelitis optica may be distinguished from typical multiple sclerosis on the basis of key clinical and neuroimaging characteristics in addition to detection of NMO-IgG. The disease has an even stronger female predilection than does multiple sclerosis, with a reasonably consistent female to male gender ratio of >3:1 reported from samples of diverse racial and regional populations worldwide. The gender distribution appears to be similar in both childhood-onset and adult-onset cases. Female gender is associated with a relapsing course and familial disease, but the influence of gender on disease severity and treatment response are not clear. Population-based epidemiological and genetic studies, with case ascertainment aided by the high specificity of NMO-IgG and consistent disease definitions, are needed to better define and understand gender effects in neuromyelitis optica.