Background: Randomised trials recently showed that sequencing of first-line (1 L) immune checkpoint inhibitor (ICI) and second-line (2 L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAF^V600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2 L BRAF/MEKi are limited as the combination was developed for 1 L use, lacking estimates for the impact of prior ICI. Methods: This retrospectively study analysed 2343 patients from the EUMelaReg registry with BRAF^V600-mutated melanoma who received BRAF/MEKi either as 2 L after failing 1 L ICI (n = 654) or as 1 L treatment (n = 1689). Patients with prior adjuvant ICI or BRAF/MEKi were excluded. Prognostic imbalances between the two groups were adjusted using 1:1 inverse propensity score matching. Key efficacy outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and time on treatment (TOT). Results: Patients in the 2 L cohort achieved outcomes from start of treatment at least equivalent to the matched 1 L BRAF/MEKi cohort. Kaplan-Meier estimates demonstrated longer median PFS (8.4 vs 7.7 months; p = 0.01) and longer median TOT (7.8 vs 6.2 months; p = 0.002) for patients treated with 2 L BRAF/MEKi compared to 1 L. Median OS from start of 2 L (17.2 months) or 1 L (16.0 months) BRAF/MEKi was similar (p = 0.73) despite inherent bias from differing index dates. ORR among both groups (56.4 % vs 53.5 %; p = 0.32) was equal. Conclusion: This study further supports the recommended sequencing of ICI as 1 L and BRAF/MEKi as 2 L therapy for patients with BRAF^V600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.