Background: Adjuvant treatment with anti-PD1 therapy improves the recurrence free survival (RFS) in resectable stage III melanoma. The Checkmate-238 and KEYNOTE-054 trials respectively reported a 4-year RFS of 52.5% for adjuvant nivolumab and a 3-year RFS of 63.7% for adjuvant pembrolizumab. Despite these improved outcomes, a considerable proportion of patients have a relapse in the years after therapeutic lymph node dissection (TLND). The OpACIN trial showed that neoadjuvant treatment with nivolumab (NIVO) plus ipilimumab (IPI) is feasible and induces a stronger and broader T-cell response. The subsequent OpACIN-neo trial identified 2 cycles of NIVO 3mg/kg + IPI 1mg/kg as a neoadjuvant dosing scheme with decreased toxicity and preserved high pathologic response rates (77%), which was confirmed in the PRADO trial. A favorable 2-year RFS (83,6%) was achieved in the overall OpACIN-neo population, although patients with a pathological partial or non-response have a worse prognosis and may therefore benefit from additional adjuvant therapy. The efficacy of neoadjuvant checkpoint inhibition versus the current standard of adjuvant therapy needs to be confirmed in a phase III trial, before neoadjuvant therapy can be considered as a standard option for this patient population. Methods: This international, randomized phase 3 trial aims to compare the efficacy of neoadjuvant IPI + NIVO with adjuvant NIVO in macroscopic stage III melanoma. In total 420 patients diagnosed with recurrent or de novo melanoma, with at least one pathologically proven, clinically detectable lymph node (up to 3 in-transit metastases (ITMs) allowed), will be randomized to neoadjuvant or adjuvant treatment. The population will be stratified by BRAF mutation, continent and the presence of ITMs. Patients in arm A will receive 2 cycles of IPI 80mg + NIVO 240mg and will undergo TLND at week 6. In the case of pathological partial response or non-response, surgery will be followed by adjuvant NIVO (11 cycles) or adjuvant dabrafenib + trametinib (46 weeks) if BRAFV600-mutation is present. Patients in arm B will undergo upfront TLND followed by 12 cycles of NIVO 480mg. The primary endpoint will be the event free survival (EFS) defined as the time from randomization until progression to unresectable stage III or stage IV melanoma, recurrent melanoma, a new primary melanoma or death due to melanoma or treatment. Final analysis will be performed after 132 events have been observed, or at latest 2 years after the last patient is included. Baseline biopsies and blood samples (screening, week 0, 3, 6, 9 and 12) will be collected for translational research. Quality of Life questionnaires and electronic Patient Reported Outcomes will be collected using the Kaiku application. The first patient was enrolled on the 23rd of July 2021. Clinical trial information: NCT04949113.