Background: Neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) showed improved event-free survival compared to adjuvant (adj) NIVO, but at the cost of increased immune related toxicity (irAEs). In the PRADO trial, impairment of health-related quality of life (HRQoL) was predominantly driven by the extent of the surgery and not by irAEs. To evaluate the effect of neoadj IPI+NIVO on HRQoL, we report the 36w HRQoL outcomes from the phase 3 NADINA trial. Methods: Eligible patients (pts) with resectable, macroscopic stage III melanoma were randomly assigned to receive 2 cycles of neoadj IPI+NIVO followed by a therapeutic lymph node dissection (TLND; w6) and only in partial- or non-responders, 1y of adj systemic treatment; or TLND (w0) followed by 12 cycles adj NIVO. EORTC QLQ-C30 questionnaires (qtn) were digitally collected at baseline, w6, w12 and thereafter q12w. The unadjusted HRQoL scores (scale 0-100) were assessed for pts who completed 39w of follow-up (FU) on January 12, 2024. Results: 261/423 randomized pts had 39w FU at data cutoff. 81% completed the qtn at BL, with thereafter an average compliance of 80%. QLQ-C30 data were available for 107 pts in the neoadj arm and 103 in the adj arm. Physical-, role-, emotional functioning, and pain were comparable between the neoadj and adj arm across all timepoints (Table), as were fatigue and the summary score. A numerical trend towards worsening of physical-, role functioning, and pain was seen at w6 for the adj arm and at w12 for the neoadj arm, representing the post-surgery QoL timepoints. Conclusion: Using fully digitalized data collection, this first HRQoL analysis of neoadj vs adj immunotherapy in stage III melanoma showed comparable results between the neoadj and adj arms. Physical-, role functioning, and pain were impaired in both groups at the first post-surgery timepoint. Clinical trial information: NCT04949113.