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Stiff-person syndrome is a rare neurologic disorder characterized by fluctuating and progressive stiffness of axial and limb musculature. The high prevalence of autoantibodies and associated autoimmune diseases in patients with stiff person syndrome suggests that it may have an autoimmune etiology. We report a case of a 62-year-old man with diabetes who developed progressive stiffness of the hips and legs and elevated levels of antibody to glutamic acid decarboxylase. He had a partial response to both baclofen and diazepam, but could not tolerate the treatment because of somnolence. He eventually received 2 infusions of rituximab 1000 mg a week apart. The baclofen was discontinued and the diazepam was tapered. However, 6 months after the rituximab treatment, despite continued clinical improvement the patient had persistently elevated titers of antibody to glutamic acid decarboxylase. We postulate that rituximab was associated with clinical improvement through mechanisms other than antibody depletion.