Background: To explore the prognostic value of TP53 co-mutation with EGFR or KRAS in advanced non-small cell lung cancer. Methods: 314 patients with advanced non-small cell lung cancer (NSCLC) admitted to the Department of Oncology of the Fourth Hospital of Hebei Medical University from January 2016 to January 2021 were retrospectively analyzed, all with complete genetic information.According to the analysis results, EGFR and KRAS were identified as co-mutated genes.TP53 mutation was used as the experimental group and TP53 wild as the control group.Patients in TP53 mutation group were further classified and discussed according to different exon 4, 5, 6, 7, 8, other mutations and mutations could not be classified.Co-mutation group was studied according to TP53/KRAS mutation status, and according to KRASG12 mutation, Patients were divided into TP53/KRASG12C (wt/wt), TP53/KRASG12C (wt/mut), TP53/KRASG12C (mut/mut) and TP53/KRASG12C (mut/mut) for further grouping.In the study of TP53/EGFR co-mutation, TP53/EGFR mutation status was divided into groups, and subgroup analysis was conducted according to different TP53 exon mutations.SPSS 26.0 software was used to analyze the data, and P < 0.05 indicated statistical difference. Results: The frequency of single gene mutation in 314 patients was analyzed. The most common mutation was TP53 (64.3%), followed by EGFR (49.4%).TP53wt group compared with TP53mut group OS (34.3m vs 28.9m;HR = 1.263, 95% ci: 0.933 1.709;P = 0.131).The OS of Exon4 group was 23 months, Exon8 group was 44.5 months, and TP53wt group was 34.3 months, no statistical significance was observed (P = 0.159).In the TP53/KRAS co-mutation group, the median OS of KRAS/TP53 (mut/mut) group and KRAS/TP53 (wt/wt) group was 29.4m vs 34.3m; HR = 2.482, 95%Cl:1.378-4.471, P = 0.002).In subgroup analysis, the median OS of KRASG12Cmut/TP53mut group and KRASG12Cmut/TP53wt group were (8.9m vs 34.9m; HR = 38.268, 95%CL: 8.359-175.183, P = 0.199), (3.1m vs 34.3m;HR = 2.572, 95%Cl:1.344-4.922,P = 0.004).In the TP53/EGFR co-mutation group, the median OS of EGFRmut/TP53mut, EGFRwt/TP53mut, EGFRmut/TP53wt and EGFRwt/TP53wt were 32.9, 17.9, 42.7 and 31.2 months, respectively (P = 0.004).In subgroup analysis, the median OS of EGFRmut/ TP53Exon4-mut versus EGFRwt/TP53wt group was (25.8m vs 31.1m; HR = 2.909, 95%Cl: 1.438-5.886, P = 0.003). Conclusions: TP53 is a factor of poor prognosis in NSCLC patients, patients with TP53/KRAS co-mutation have poor survival, and kRASG12C-mut /TP53mut subgroup have worse prognosis.Patients with TP53/EGFR co-mutation had a better prognosis, and the EGFRmut/ TP53Exon4-mut subgroup had the worst prognosis.