Background: MUC16 is frequently mutated in non-small cell lung cancer (NSCLC). Previous studies showed MUC16 mutation were associated with TMB and prognostic outcome in gastric cancer patients and may benefits for patients with immunotherapy. Herein, we aimed to characterize the association of MUC16 with immunotherapy biomarkers in Chinese and Western NSCLC patients. Methods: Next-generation sequencing data and clinical data were collected from 1053 TCGA NSCLC patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 1056 Chinese pan-cancer patients (Chinese cohort). Both MUC16 mutation ratio and TMB were calculated on the two cohorts following the same criteria. Results: In total, 269 (25%) of the 1056 Chinese patients and 494 (47%) of the 1053 Western patients had at least one mutation of MUC16 genes (MUC16 mutant group). The Chinese cohort had a higher mutation frequency of MUC16 gene than the Western cohort (25% vs. 47%, p＜0.001). In both cohorts, TMB was higher in the MUC16 mutant group compared to non-MUC16 mutant group. In Chinese cohort, PD-L1 positive was not associated with MUC16 mutation. However, patients with MUC16 mutation were not associated with prolonged survival in Western immunotherapy cohort. Conclusions: Our study provided a landscape of MUC16 mutations in a much larger Chinese NSCLC group, which could be a valuable complement to TCGA dataset. Both in Chinese and Western cohorts, the higher TMB in MUC16 mutant patients suggested potential efficacy from immunotherapy of MUC16 mutant group. A larger validation cohort of MUC16 mutant is required to confirm these findings in the further.