【Abstract】Objective?To observe the effect of apatinib combined with paclitaxel and cisplatin (TP) chemotherapy regimen in the treatment of patients with driver-gene-negative advanced non-small cell lung cancer (NSCLC), and analyze the related factors affecting the efficacy, so as to provide the reference for clinical practice. Methods?80?patients with driver-gene-negative advanced NSCLC who were treated in Nanjing First Hospital, Nanjing Medical University from August 2020?to December 2021?were selected as the research objects for retrospective analysis. All patients were treated with apatinib combined with TP chemotherapy regimen. The therapeutic effect was observed and divided into effective group (68?cases) and ineffective group (12?cases) according to different therapeutic effects, and the independent risk factors affecting the therapeutic effect were analyzed. Results?After treatment, 6?patients had complete remission, 40?patients had partial remission, 22?patients had stable disease, and 12?patients had progressive disease. The proportion of highly differentiated tumors in the effective group was higher than that in the ineffective group, the proportion of pathological stage Ⅳ was lower than that in the ineffective group, and the levels of carcinoembryonic antigen (CEA), cytokeratin 19?fragment (CYFRA21-1), neural specific enolase (NSE), and neutrophil-lymphocyte ratio (NLR) in the effective group were lower than those in the ineffective group (P<0.05). Multivariate Logistic regression analysis showed that the pathological stage of Ⅳand the increase levels of CEA, CYFRA21-1, NSE, NLR were independent risk factors for the efficacy of patients with driver-gene-negative advanced NSCLC (P<0.05). The high degree of tumor differentiation was an independent protective factor for the efficacy of patients with driver-gene-negative advanced NSCLC (P<0.05). Conclusion?Apatinib combined with TP chemotherapy has good efficacy in the treatment of patients with driver-gene-negative advanced NSCLC, but it should be paid more attention to clinically due to the influence of pathological stage, tumor differentiation degree and CEA, CYFRA21-1, NSE and NLR levels.