Background: Mucin (MUC) is a family of high-molecular weight glycoproteins and increased mucin production occurs in many malignant tumors. Recent studies have found relationship between mutations of some MUC family genes and efficacy of immunotherapy. Here, we explored the associations of MUC family genes (MUC2, MUC3A, MUC4, MUC5B, MUC6, MUC12, MUC16, MUC17, MUC19) mutation with ICI response based on multidimensional data from multiple solid tumors. Methods: 15 solid tumor types of TCGA genomic data for 6138 patients was used to evaluate tumor mutational burden (TMB) differences between MUC family genes mutation group and wildtype group. TMB was calculated as the total count of nonsynonymous mutations in coding sequence. Neoantigens of 3039 samples across 11 solid tumor types were obtained from The Cancer Immunome Atlas. A pan-cancer immunotherapy cohort (Broad/Dana-Farber, Nat Genet 2018, N = 249) was used to explore the relationship between mutations of MUC family genes and its efficacy of immunotherapy. Results: The most common mutated MUC genes (frequency > 5%) were MUC16 (25.3%), MUC17 (10.8%), MUC5B (10.5%), MUC4 (8.6%), and MUC2 (5.1%). The data between MUC mutation group and wild type group showed a significant difference (P < 0.01) in TMB. Median TMB across fifteen tumors in MUC mutation group and wild type group is 7.04 mutations per Mb and 2.07 mutations per Mb, separately. The TNB between two group is also showed a significant difference (P < 0.01). Median TNB across nine types tumor in MUC mutation group and wild type group is 121.5 neoantigens and 34.0 neoantigens, separately. A multivariable analysis across the pan-cancer cohort using Cox proportional-hazards regression demonstrated that KMT2C mutation was associated with better OS (hazard ratio, 0.66; 95%CI, 0.45-0.99; P = 0.042), adjusting for sex and cancer type. Conclusions: The results indicated that MUC family genes mutation was associated with a higher TMB and TNB. Analysis of immunotherapy cohort data showed MUC family was associated with better OS. These findings indicate that these genes mutation may serve as a predictive biomarker for ICI in solid tumor patients.