Background: MUC16 is a mucin marker that is frequently mutated in melanoma, but whether MUC16 mutations could be useful as a surrogate biomarker for tumor mutation burden (TMB) remains unclear. Methods: This study rigorously evaluates the MUC16 mutation as a clinical biomarker in cutaneous melanoma by utilizing genomic and clinical data from patient samples from The Cancer Genome Atlas (TCGA) and two independent validation cohorts. We further extended the analysis to studies with patients treated with immunotherapies. Results: Analysis results showed that samples with MUC16 mutations had a higher TMB than the samples of wild-type, with strong statistical significance (P < 0.001) in all melanoma cohorts tested. Associations between MUC16 mutations and TMB remained statistically significant after adjusting for potential confounding factors in the TCGA cohort [OR, 9.28 (95% confidence interval (CI), 5.18–17.39); P < 0.001], Moffitt cohort [OR, 31.95 (95% CI, 8.71–163.90); P < 0.001], and Yale cohort [OR, 8.09 (95% CI, 3.12–23.79); P < 0.01]. MUC16 mutations were also found to be associated with overall survival in the TCGA [HR, 0.62; (95% CI, 0.45–0.85); P < 0.01] and Moffitt cohorts [HR, 0.49 (95% CI, 0.28–0.87); P = 0.014]. Strikingly, MUC16 is the only top frequently mutated gene for which prognostic significance was observed. MUC16 mutations were also found valuable in predicting anti–CTLA-4 and anti–PD-1 therapy responses. Conclusions: MUC16 mutation appears to be a useful predictive marker of global TMB and patient survival in melanoma.