Immune-mediated inner ear disease (IMIED) is one of the few forms of reversible sensorineural hearing loss. Corticosteroids-responsive patients are usually associated with hearing improvement. Due to the long clinical course of IMIED that frequently present recurrences (hearing loss and vertigo), alternatives to corticosteroids such as methotrexate and recently TNF-alpha blockers have been proposed. Likewise new procedures for delivering corticosteroids to the inner ear have been developed. The aim of this article is to assess the efficacy of methotrexate and transtympanic 6-methylprednisolone in refractory IMIED. From a database of 200 patients affected by IMIED, 16 selected patients with refractory disease were included in the present study. Five patients were treated with methotrexate and 11 by means of transtympanic injection of 6-methylprednisolone. All patients treated with methotrexate had an improvement in their vestibular symptoms. However, hearing loss did not improve. Most patients treated with local 6-methylprednisolone (68.75%) showed an improvement in hearing loss and vestibular symptoms. Methotrexate has been shown to be ineffective in maintaining long-term remissions of hearing relapses although patients presented an improvement in vestibular symptoms. However, transtympanic 6-methylprednisolone has been shown to be a safe, easy and useful therapy in refractory IMIED and it may actually become the first-line treatment for these patients based on the existence of glucocorticoid receptors and the possible targets of immune-mediated damage within the inner ear.