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Abstract Background While drug reactions to rituximab have been commonly reported in the literature, a type I allergic reaction to rituximab after first lifetime exposure has never been reported. Case presentation We describe a case of a 58-year-old female patient who received rituximab for the first time for treatment of rheumatoid arthritis. She developed symptoms immediately after infusion, however presented 11 days after drug exposure with cyclical anaphylaxis-like reaction requiring multiple doses of epinephrine. On second exposure, she experienced immediate anaphylaxis 30 min into infusion. Conclusion Our case illustrates the importance of heightened awareness by physicians that type I IgE-mediated reactions after first exposure to monoclonal antibodies such as rituximab are possible, and if unrecognized, could be potentially life-threatening.