Immunotherapies have dramatically improved survival outcome for patients with melanoma. MUC16 encodes cancer antigen 125 (CA125), which is frequently mutated in melanoma. In this study, we correlated the MUC16 mutational status with the following: tumor mutation burden (TML), multiple immune-related signals in microenvironment, deregulated pathways, survival outcome, and immunotherapeutic efficacy. We found that patients with MUC16 mutations had significantly higher TML than those without it. Enriched pro-inflammatory CD8 T cells and M1 macrophages, enhanced interferon gamma (IFNγ) and T cell-inflamed signatures, and increased cytolytic activity were associated with MUC16 mutations. Immune-suppressive M2 macrophages were enriched in patients with wild-type MUC16. Immune checkpoints expression (e.g., PD-L1, PD-1 and CTLA-4) was also elevated in patients with MUC16 mutations. Immune response relevant circuits were among the top enriched pathways in samples with MUC16 mutations. Patients with MUC16 mutations exhibited a significantly better prognosis. For patients who received immunotherapy, the presence of MUC16 mutations was associated with a better response rate and survival outcome in male patients but not in female or overall patients. These findings provide new implications for tailoring immunotherapeutic strategies for melanoma patients.