Background: The pivotal phase 3 EPITOPE trial, a 12-month, double-blind, placebo-controlled study of epicutaneous immunotherapy with the VIASKIN patch containing 250 μg of peanut protein (VP250), previously reported significant treatment response versus placebo in peanut-allergic toddlers aged 1 through 3 years. Objective: To assess the interim efficacy and safety of VP250 from the first year of the EPITOPE open-label extension (OLE) study. Methods: Eligible participants enrolled in the OLE study for up to 3 years of total treatment with annual double-blind, placebo-controlled food challenges (DBPCFCs) and safety assessments; here we report the first-year OLE (year 2) results. Results: A total of 266 EPITOPE participants enrolled in the OLE study; 244 underwent month 24 DBPCFC (n = 166 VP250; n = 78 placebo). After 24 months of VP250, 81.3% reached an eliciting dose (ED) ≥1000 mg, 63.8% reached an ED ≥2000 mg, and 55.9% completed the DBPCFC (cumulative dose: 3444 mg) without meeting stopping criteria. No treatment-related anaphylaxis or serious treatment-related adverse events occurred during year 2 in this treatment arm. Local application-site reactions occurred less frequently in year 2 versus year 1. In placebo-treated EPITOPE participants, outcomes after 1 year of open-label VP250 were consistent with EPITOPE treatment results: 62.7% reached an ED ≥1000 mg, 36.5% reached an ED ≥2000 mg, and 28.4% completed the DBPCFC without meeting stopping criteria; and there was 1 treatment-related anaphylaxis event. Conclusions: Two years of VP250 in young peanut-allergic children demonstrated continued increases in treatment effect without new safety signals. This supports the potential of VP250 as a safe and effective treatment for peanut allergy in young children. Clinicaltrials.gov: NCT03859700.