Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON. Display omitted •LEROS meets its primary endpoint based on clinically relevant benefit at month 12•Favorable outcomes are observed to month 24, regardless of disease phase•Treatment effect is influenced by disease phase, mtDNA mutation, age, and gender•LEROS confirms a favorable safety profile of idebenone in LHON patients Yu-Wai-Man et al. demonstrate how idebenone can positively affect vision in patients with Leber hereditary optic neuropathy (LHON) in the LEROS study. A clinically relevant benefit is observed in significantly more eyes from patients treated with idebenone compared to those from untreated patients in a historical comparator group.