BACKGROUND: Germline mutations in numerous genes, particularly tumor suppressor genes, markedly heighten the risk of various cancers, including lung cancer, which is the leading cause of cancer-related deaths worldwide. Despite extensive research on well-known genes like BRCA1, BRCA2, and mismatch repair genes, many genetic factors contributing to cancer susceptibility remain unidentified. METHODS: This study reviewed sequencing data from 4,934 Chinese lung cancer patients. Matched white blood cell samples were sequenced using WES or gene panels to identify germline mutations. Analysis included statistical tests to compare patient demographics, clinical characteristics, and somatic mutation profiles. RESULTS: Among the cohort, 89 patients carried pathogenic/likely pathogenic (P/LP) germline mutations in 20 known cancer susceptibility genes, with ATM, BRCA2, and CHEK2 being the most common. TP53 mutations were linked to early-onset lung cancer, while ATM mutations correlated with late-onset and higher PD-L1 expression, suggesting immunotherapy benefits. Germline mutations were more prevalent in younger patients and females. Somatic mutation profiles showed similarities in common mutations but differences in MTOR (p = 0.044) and MSH6 (p = 0.018) mutations in P/LP carriers. GO and KEGG analyses indicated distinct biological processes and pathways in patients with P/LP germline mutations. Gene exclusivity analysis revealed correlations and mutual exclusivity between specific germline and somatic mutations. Comparative analysis with the gnomAD database showed a higher prevalence of these mutations in lung cancer patients compared to the general and East Asian populations, suggesting an association with increased lung cancer risk in the Chinese cohort. CONCLUSION: This study underscores the prevalence of germline mutations in Chinese lung cancer patients, identifying significant associations with clinical characteristics and somatic mutation profiles. The findings highlight the importance of considering germline mutations in lung cancer treatment and the potential benefits of personalized therapy based on genetic susceptibility.