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Background Lenadogene nolparvovec is an intravitreal gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A MT-ND4 variant. Idebenone, a synthetic coenzyme Q10 analogue, is the only approved treatment for LHON. To estimate the relative effects of both treatments, we performed two matching adjusted indirect comparisons (MAICs) between idebenone aggregated data from the LEROS study and expanded access programme (EAP), and lenadogene nolparvovec individual data from the REFLECT study (bilateral treatment).Methods Matching covariates included age at disease onset, sex, baseline best-corrected visual acuity (BCVA), and time from vision loss to treatment. The outcomes of interest were clinically relevant recovery (CRR) from nadir at 24 months, time to initial CRR and change from baseline BCVA at 24 months.Results For the MAIC LEROS versus REFLECT (effective sample size (ESS): 77), a statistically higher CRR at 24 months was observed with lenadogene nolparvovec compared with idebenone (60.4% vs 35.4%; OR=2.78, 95% CI 1.53 to 5.06; p=0.001). No statistically significant difference was observed for time to initial CRR and change from baseline BCVA at 24 months. For the MAIC EAP versus REFLECT, there was a low overlap between the two populations related to a difference in the time from vision loss to treatment. In a post hoc sensitivity analysis comparing EAP to RESCUE data (ESS: 33), CRR was 39.0% for idebenone versus 69.5% for lenadogene nolparvovec (OR=3.59, 95% CI 1.42 to 9.06; p=0.011).Conclusion The two MAICs demonstrated a clinically meaningful higher visual recovery at 24 months with lenadogene nolparvovec than with idebenone in patients with LHON due to the m.11778G>A MT-ND4 variant.