We present a case of a woman with systemic lupus erythematosus (SLE) who had refractory episodes of neuromyelitis optica spectrum disorder (NMOSD) and was successfully treated with rituximab. She was positive for anti-aquaporin-4 (AQP4) antibody and had typical cranial and longitudinally extended spinal lesions but no optic nerve involvement. There is no established treatment for NMOSD/SLE overlap cases. Our experience suggests that rituximab may be effective for patients with combined SLE and anti-AQP4 antibody-positive NMOSD.