We report a case of a 66-year-old Caucasian female with a diagnosis of idiopathic orbital inflammatory disease (OID) refractory to azathioprine therapy. The coexistence of diabetes mellitus represented a relative contraindication to chronic prednisone use. After two infusions of rituximab, a chimeric anti-CD20+ antibody, ophthalmic signs and symptoms remarkably improved. To our knowledge, this is the first case of idiopathic OID successfully treated with rituximab.