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Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology, and the limited available therapeutic options for this disease, are frustrating to both clinicians and patients. However, recent advances in the understanding of disease mechanisms have given rise to numerous studies on specific approaches to SLE treatment. Rituximab, the first chimeric, mouse-human monoclonal antibody which is directed against CD20, seems to be a new therapeutic option. The purpose of this review is to explain the current clinical evidence on the therapeutic use of rituximab in adult SLE patients. Two randomized clinical trials with rituximab (the EXPLORER and LUNAR studies) failed to prove efficacy of this drug on SLE. Ongoing data analysis continues to explain the reasons behind why this treatment fails to work. However data from open source and observational studies contrast with clinical trials results. The global analysis of this data supports the off-label use of rituximab in subsets of SLE that are refractory to standard treatment.