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We report the case of a 9-year-old boy with severe hemophilia B with an inhibitor and a history of anaphylaxis to factor IX (FIX), who was successfully treated with immune tolerance (IT) that included rituximab (Genentech, San Francisco, CA) and desensitization. The patient began the first course of IT at age of 7 years with daily recombinant FIX infusions that was aborted at day 32 because of a systemic allergic reaction. A second course of IT was attempted 11 months later, initiated with a desensitization protocol with escalating doses of plasma-derived FIX in addition to therapy with rituximab. This was well tolerated without allergic symptoms and with eradication of the inhibitor and improvement in factor kinetics. A second course of rituximab was given 13 months later for worsening FIX kinetics again with an excellent response and without evidence of adverse effects.