BACKGROUND Patients with late-onset systemic lupus erythematosus (SLE) do not present with typical SLE symptoms or serology, and this can lead to a major delay in diagnosis. We report a complex case of an older woman who developed autoimmune hemolytic anemia and sixth cranial nerve palsy that posed considerable challenges in diagnosing late-onset SLE. CASE REPORT A 78-year-old Japanese woman presented with polyarthritis associated with generalized fatigue for 2 months, who later developed diplopia. Physical examination revealed conjunctival pallor, polyarthritis, and subsequent development of sixth cranial nerve palsy. Laboratory data revealed a decreased white blood cell count; macrocytic anemia; elevated levels of lactate dehydrogenase, indirect bilirubin, and erythrocyte sedimentation rate; hypocomplementemia; positive Coombs test; antinuclear antibodies (ANAs, 1: 40); and positive anti-double-strand DNA antibodies. Lymphoma, cerebral venous sinus thrombosis, and varicella-zoster virus infection were unlikely based on head computed tomography, brain magnetic resonance imaging, and cerebrospinal fluid analysis. She was diagnosed with late-onset SLE associated with autoimmune hemolytic anemia and sixth cranial nerve palsy. The patient was successfully treated with prednisone and hydroxychloroquine. CONCLUSIONS The difficulty in diagnosing late-onset SLE with atypical presentations and uncommon complications must be recognized. SLE cannot be excluded based on a low titer of ANA in a particular subgroup such as the elderly, and the prozone effect should be considered responsible for low ANA titers. In this case, late-onset SLE was diagnosed by considering multisystem pathologies despite low ANA titers.