BACKGROUND: Systemic glucocorticoids are commonly used for primary therapy of idiopathic sudden sensorineural hearing loss (ISSNHL). However, the comparative effectiveness and risk profiles of high-dose over lower-dose regimens remain unknown. METHODS: We randomly assigned patients with sudden hearing loss of greater than or equal to 50 dB within 7 days from onset to receive either 5 days of high-dose intravenous prednisolone at 250 mg/d (HD-Pred), 5 days of high-dose oral dexamethasone at 40 mg/d (HD-Dex), or, as a control, 5 days of oral prednisolone (Pred-Control) at 60 mg/d followed by 5 days of tapering doses. The primary outcome was the change in hearing threshold (pure tone average) in the three most affected contiguous frequencies from baseline to day 30. Secondary outcomes included speech understanding, tinnitus, communication competence, quality of life, hypertension, and insulin resistance. RESULTS: A total of 325 patients were randomly assigned. Mean change in 3PTAmost affected hearing threshold from baseline to 30 days was 34.2 dB (95% CI, 28.4 to 40.0) in the HD-Pred group, 41.4 dB (95% CI, 35.6 to 47.2) in the HD-Dex group, and 41.0 dB (95% CI, 35.2 to 46.8) in the Pred-Control group (P=0.09 for analysis of variance). There were more adverse events related to trial medication in the HD-Pred (n=73) and HD-Dex (n=76) groups than in the Pred-Control group (n=46). CONCLUSIONS: Systemic high-dose glucocorticoid therapy was not superior to a lower-dose regimen in patients with ISSNHL, and it was associated with a higher risk of side effects. (Funded by the Federal Ministry of Education and Research [BMBF]; EudraCT number, 2015‐002602‐36.)