Summary Background Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. Methods This prospectively-powered multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity. Findings We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n=393 [66%]) or PD-1 (n=205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21-43), the median RFS was 51∙0 months (95%CI 41∙0-not reached [NR]) in the D/T group, significantly longer than 44∙8 (95%CI 28∙5-NR) in the PD-1 group (univariate: HR 0∙658, 95%CI 0∙498-0∙869, P=0∙003; multivariate: HR 0∙687, 95% CI 0∙512-0∙922, P = 0∙012), with comparable OS with PD-1 (multivariate, HR 1∙011, 95%CI 0∙637-1∙604, P>0∙95). Similar findings were observed using a restricted-mean-survival-time model. D/T survival benefits were consistent in most subgroups, except for older, male patients and those with V600K mutation. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs. Interpretation In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T is potentially a superior adjuvant option compared with PD-1.