AbstractPurpose: LHON is a rare mitochondrial disorder which results in bilateral vision loss. Idebenone is approved in Europe for the treatment of LHON, but relatively little controlled data exists to support use in chronic patients. Here, we report primary results from LEROS, a Phase 4, externally controlled interventional study in patients with chronic LHON (1 to ≤5 years since onset) treated with idebenone for up to 24 months.Methods: Patients with LHON onset ≤5 years prior were enrolled and stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 but ≤5 years). Visual acuity (VA) outcomes from 181 patients, treated for up to 24 months were compared to retrospective data from an external natural history (NH) cohort (N = 372) matched by time since onset. Outcome measures, from baseline, were clinically relevant recovery (CRR): improvement from ‘off‐chart’ VA to at least 1.6 logMAR, or a ≥0.2 logMAR improvement if already ‘on‐chart’; clinically relevant stabilization (CRS): maintenance of VA <1.0 logMAR; and clinically relevant benefit (CRB): reaching a CRR, a CRS, or both.Results: As was observed in the subacute/dynamic phase, the frequency of a CRB from baseline at 12 months was significantly higher in treated, chronic eyes than in matched NH eyes (50.3% [72/143] vs. 38.6% [59/153] [p = 0.0087]). This difference was largely driven by a higher proportion of eyes with a CRR of visual acuity (VA) (32.9% [47/143] vs. 19.6% [30/153] [p = 0.0034]). The distribution of patients between VA categories changed over the study duration. At baseline, 34.5% of patient's best VA was off‐chart, with 35.6% between 1.0–1.68 logMAR, and 29.9% < 1.0 logMAR. By 24 months, these proportions had changed to 16.4, 41.8 and 41.8%, respectively.Conclusions: LEROS provides evidence of a significant therapeutic benefit of idebenone treatment in patients with LHON in the chronic stage up to 5 years from onset.