Tumor mutation burden (TMB) is an independent indicator used to select patients sensitive to immunotherapy. The present study aimed to investigate the clinicopathological and molecular characteristics of patients with hypermutant lung cancer to identify an economical, simple and complementary method for predicting TMB and immunotherapy responses. In total, 1,000 patients with lung cancer were randomly selected, and their samples were submitted to next-generation sequencing, with their TMB status reviewed. The threshold of hypermutation was set to 17.24 mutations (muts)/Mb. The proportion of smokers was higher in the hypermutant cohort (n=67) compared with in the non-hypermutant cohort (n=933; 85.1 vs. 46.6%; P<0.0001). Compared with in the non-hypermutant cohort, the proportion of squamous cell carcinoma cases and small cell lung cancer cases was higher in the hypermutant cohort (22.4 vs. 13.1% and 6.0 vs. 2.6%, respectively). In addition, compared with in the non-hypermutant cohort, mutations in the low-density lipoprotein receptor-related protein 1B were more frequently observed in the hypermutant cohort (67.2 vs. 14.3%; P<0.0001). A similar trend was obtained for all genes tested, except for the EGFR gene. Furthermore, in the hypermutant cohort, the prevalence of microsatellite instability was extremely high (9.0%). The mutation frequency in DNA damage response (DDR) genes was notably higher in the hypermutant cohort, where several DDR-associated genes were enriched, compared with in the non-hypermutant cohort. The enrichment analysis revealed a strong association between mutations in Notch signaling and high TMB. To the best of our knowledge, the present study is the first to comprehensively investigate the clinical and genetic characteristics of patients with hypermutant lung cancer in a Chinese population. The results of the current study suggested that hypermutant lung cancer exerted distinctive clinical and genetic features, which may be used as complementary indicators for screening patients sensitive to immunotherapy. Copyright: © Zhang et al.