Multiple sclerosis and neuromyelitis optica spectrum disorder are currently thought to be independent entities. Some patients display intermediate manifestations that fit the criteria for both diseases without positive relevant serobiomarkers. An overall standard and consensus for the diagnosis and treatment of these overlapping patients have not been reached. We describe a patient with frequently relapsing demyelinating episodes and repeatedly adjusted treatment regimens due to diagnostic difficulties. This case did not respond adequately to glucocorticoid plus azathioprine or to interferon. Benefits were finally obtained by using rituximab, an anti-CD20 specific monoclonal antibody targeting B cells. Treatments targeting B cell mediated humoral immunity such as rituximab, may be a safe and appropriate choice for these challenging demyelinating cases, especially in Asian population.