Objectives: MUC16, a mucin marker with a high mutation probability, is closely related to the occurrence, development, response to treatment, and prognosis of melanoma. As melanoma has high immunogenicity, immunotherapy has become a routine treatment. Tumor mutation burden (TMB) is the most common indicator for determining appropriate immunotherapy. The relationship between the mutation and expression of MUC16 and the prognosis, TMB, level of immune infiltration, and drug sensitivity in melanoma was investigated in this study. Methods: Melanoma data were downloaded from the Cancer Genome Atlas and the International Cancer Genome Consortium database, and the “GenVisR” package was used to visualize the gene mutation types and frequencies. Intersections of the top 30 genes with the highest mutation frequencies were determined. Thereafter, we investigated the effects of MUC16 mutations on overall survival (OS) and TMB of melanoma patients by multivariate Cox regression and multivariate logistic analyses. Related pathways that were enriched by MUC16 and BRAF were investigated using gene-set enrichment analysis and gene-set variation analysis. The CIBERSORT calculation method was used to analyze the proportion of tumor-infiltrating immune subsets. The relationship between MUC16 expression and drug sensitivity was also discussed. Results: Twenty-two genes with high mutation frequencies were identified in both datasets. MUC16 and ADGRV1 mutations were associated with higher TMB and good clinical prognosis (P