Objective To explore the value of peripheral blood circulating DNA in predicting the efficacy and prognosis of immunotherapy for advanced non-small cell lung cancer. Method A retrospective study was conducted on 78 NSCLC patients who were admitted to the Respiratory and Critical Care Medicine Department of the First Affiliated Hospital of Hebei North University and were treated with tirelizumab for advanced driver gene negativity from January 2021 to December 2021. After 2 cycles of immunotherapy， the efficacy was evaluated according to the Solid Tumor Efficacy Evaluation Criteria （RECIST 1.1）， including complete remission， partial remission， disease stability， and disease progression. CR and PR patients were defined as the experimental group （n = 48） Other patients were defined as the control group （n = 30）， and the ctDNA levels in peripheral blood were measured before and after treatment in both groups. ROC curves were used to analyze the predictive value of peripheral blood ctDNA levels for achieving objective remission after immunotherapy.All patients were followed up and their progression free survival were calcutated.Using univariate and multivariate regression analysis identified the factors affecting the prognosis of patients after immunotherapy. Using Spearman correlation coefficient analyzed the correlation between ctDNA levels and PFS. Kalplan Meier survival curve were used for survival analysis. Result The peripheral blood ctDNA levels before and after treatment in the experimental group were （4.47 ± 1.21）ng/μL and （2.65 ± 1.14） ng/μL， respectively （t = 7.559，P < 0.001）， while those in the control group were （4.54 ± 1.15）ng/mL and （4.29 ± 1.57） ng/μL， respectively （t = 0.699，P = 0.487）. There was no statistically significant difference in peripheral blood ctDNA levels between the two groups before treatment （t = -0.25，P = 0.801）. The peripheral blood ctDNA levels in the experimental group decreased compared to the control group after treatment （t = -5.35，P < 0.001）. The ROC curve analysis showed that the area under the curve for predicting objective remission after immunotherapy based on peripheral blood ctDNA levels was 0.819， with a sensitivity of 81.3% and specificity of 80%. Peripheral blood ctDNA levels were negatively correlated with progression free survival （r = -0.784，P = 0.000）. Single factor COX regression was used to analyze the clinical and pathological characteristics and ctDNA levels of enrolled patients， and the results showed that the maximum tumor diameter was greater than 5 cm （HR = 0.501， 95% CI： 6.731 ~ 35.567） Tumor stage IV （HR = 0.392，95% CI： 0.227 ~ 0.677）， treatment approach （HR = 15.473，95% CI： 6.731 ~ 35.567）， and ctDNA levels （HR = 4.657，95% CI： 3.182 ~ 6.555） are all influencing factors for PFS in advanced NSCLC patients after immunotherapy. Multiple factor analysis was conducted on the appeal indicators with statistical differences， and the results showed that treatment approach （HR = 2.981，95% CI：1.019 ~ 8.722） and peripheral blood ctDNA levels （HR = 3.918，95% CI： 2.619 ~ 5.861） It is an independent influencing factor of PFS in advanced NSCLC patients. The Kalplan Meier survival curve was used for analysis， and the results showed that the median PFS of the treatment effective group was 8.4 months， while the median PFS of the control group was 5.4 months. （χ ² = 49.277， P = 0.000）. Conclusion Immunotherapy combined with chemotherapy can enhance the ability to kill tumor cells， and peripheral blood ctDNA levels can evaluate the efficacy and prognosis of immunotherapy， which can be used to guide immunotherapy in advanced NSCLC patients.