Background: he prognosis for lung cancer patients receiving immunotherapy is impacted by hyper-progression disease (HPD). Assays for HPD-associated gene mutations were anticipated to be crucial for immunotherapy. Although easy and non-invasive, the liquid biopsy technique is not widely employed in immunotherapy. Here, we want to study details of HPD-related gene mutations in the detection of tissue and liquid biopsy and dig out some relevant information from Chinese Lung Cancer (CLC) patients. Methods: 10 genes with HPD-associated mutation were collected by literature, like SNV (EGFR, KEAP1, STK11, DNMT3A, PTEN), CNV (ALK fusion, amplification of MDM2, MDM4, FGF3, FGF4). 3540 cell-free DNA (cfDNA) samples and 6553 tumor tissue samples of LC patients download from Haplab database (HaploX, Shenzhen, China). Genetic alterations were sequenced by NGS platform and microsatellite instability status was calculated through msisensor analysis. The chi-square test was used for statistical hypothesis test. Results: In general, all mutation genes tested except EGFR were detected significantly differently between tissue and cfDNA samples (p < 0.05). 193 samples (156 tDNA, 37cfDNA) with microsatellite instability (MSI) were screened to test HPD-related gene consistency. Results showed no significant difference in 10 HPD-related genes between MSI tissue and blood samples (p > 0.05). Microsatellite stable (MSS) samples of 4499 tumor DNA and 1173 cfDNA were also performed on consistency test. EGFR and the other 4 genes (FGF3, FGF4, KEAP1, PTEN) were found consistency in tDNA and cfDNA, and ALK (p 0.0051), MDM2 (p 0.0004), MDM4 (p 0.0052), STK11 (p 0.0344), DNMT3A (p < 0.0001) showed significant difference of two type of samples. Conclusions: In overall samples and subtypes tested, only EGFR had no significant differences between tissue and cfDNA, which might make EGFR a perfect biomarker candidate in HPD detection and prognosis. Our outcomes also proved that liquid biopsy has some limitations in monitoring HPD-related genes of CLC compared with tissue biopsy. MSS patients presented more reliable results than MSI patients. When monitoring HPD-related genes except for EGFR using cfDNA, appropriate patients should be considered.