Compared to other tumor types, HYDIN (36.14%) has the highest mutation rate in melanoma patients. In the anti-PD-1 treated cohort (n = 254), the HYDIN-MUT patients had a longer OS after ICIs treatment than the HYDIN wild-type (HYDIN-WT) patients (HR = 0.590 [95% CI, 0.410-0.847], P = 0.004); the objective response rate (ORR) and durable clinical benefit (DCB) were increased in patients with HYDIN-MUT (ORR = 46.25, DCB = 56.00%) compared to patients with HYDIN-WT (ORR = 30.99%, DCB = 42.76%) (ORR: P = 0.019; DCB: P = 0.060)....HYDIN mutations are a potential predictive biomarker of ICIs efficacy in melanoma patients.