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PURPOSE: The choice of threshold and reliability of high tumor mutational burden (TMB) to predict outcomes and guide treatment choice for patients with metastatic melanoma receiving first-line immune checkpoint inhibitor (ICI) therapy in the real world is not well known. METHODS: Using a deidentified nationwide (US-based) melanoma clinicogenomic database, we identified a real-world cohort of patients with metastatic melanoma (N = 497) who received first-line monotherapy anti–PD-1 (n = 240) or dual anti–PD-1 and anti–CTLA-4 ICI (n = 257) and had a tissue-based comprehensive genomic profiling test TMB score. RESULTS: TMB-high (TMB-H; ≥10 mutations per megabase [muts/Mb], n = 352, 71%) was independently predictive of superior real-world progression-free survival and overall survival versus TMB-low (<10 mut/Mb, n = 145, 29%) in both mono ICI (hazard ratio [HR], 0.45 [95% CI, 0.32 to 0.63]; P <.001; HR, 0.61 [95% CI, 0.41 to 0.90]; P =.01, respectively) and dual ICI (HR, 0.67 [95% CI, 0.49 to 0.90]; P =.009; HR, 0.61 [95% CI, 0.42 to 0.88]; P =.007, respectively) patients. Dual ICI offered no significant advantage in BRAF wt patients and unexpectedly demonstrated greatest benefit in the TMB 10-19 mut/Mb group, identifying a TMB-very high (≥20 mut/Mb, n = 247, 50%) BRAF mut patient subgroup for whom mono ICI may be preferable. CONCLUSION: TMB-H predicts superior outcomes on ICI while coassessment of BRAF status and TMB may inform first-line regimen choice. Melanoma TMB predicts real-world ICI outcome but BRAF coassessment may better inform regimen choice. [ABSTRACT FROM AUTHOR]