AIM: To describe the authors' experience and that in the published literature regarding the use of corticosteroid sparing systemic immunosuppression for patients with corticosteroid dependent optic neuritis not associated with demyelinating disease. METHODS: The records of 10 patients from the authors' clinical database, and 38 patients from the published literature with corticosteroid dependent optic neuritis, were retrospectively reviewed to determine patient demographics, diagnosis, clinical course, and outcomes. These patients had recrudescence of symptoms, such as decreased vision and pain, with attempted taper of corticosteroid. Many of these patients also suffered side effects from systemic corticosteroid use such as weight gain and uncontrolled hyperglycaemia. Antimetabolites (for example, methotrexate and azathioprine), cyclosporine and/or alkylating agents (for example, cyclophosphamide and chlorambucil) were given to enable taper of corticosteroid while effectively controlling optic neuritis. RESULTS: The study included 43 women and 5 men: 17 patients with systemic lupus erythematosus, 12 patients with sarcoidosis, 3 with other systemic autoimmune diseases, and 16 with no clinically identifiable systemic association. 79% of all patients benefited from the use of systemic immunosuppression in that they had successful corticosteroid taper, control of inflammation, improvement in symptoms, and/or tolerance of adverse effects. Mild toxicity was common and 19% of patients, most often those taking cyclophosphamide, discontinued medication because of adverse effects. 24 of 28 (86%) patients on alkylators benefited clinically, while 20 of 29 (69%) patients on antimetabolites had clinical benefit. CONCLUSION: Systemic immunosuppression may be a safer and more effective treatment alternative to chronic oral corticosteroid use in cases of corticosteroid dependent optic neuritis not associated with demyelinating disease.