Abstract: Objective To evaluate the efficacy of sintilimab in patients with advanced non-small cell lung cancer (NSCLC) and investigate its influencing factors. Methods A total of 300 patients with advanced NSCLC admitted to the Guangdong Second Provincial General Hospital from January 2020 to January 2024 were enrolled. They received four cycles of sintilimab treatment. The efficacy, safety, and 1-year survival rate were evaluated and recorded. According to the solid tumor evaluation results, the patients were divided into the responsive group and the non-responsive group, and the clinical data of the two groups were compared. Multivariate logistic regression analysis was used to identify the factors influencing the efficacy of sintilimab in advanced NSCLC, and a logistic regression model was subsequently constructed. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of the model for efficacy. Results Among the 300 patients, 228 showed a response to treatment, and 72 did not. Overall, immune function was significantly improved after treatment compared to baseline. During treatment, 125 patients (41.67%) experienced gastrointestinal reactions, 88 (29.33%) developed myelosuppression, and 81 (27.00%) each experienced abnormal liver function and hypothyroidism. At the 1-year follow-up, the survival rate was 77.33% (232/300). Compared with the responsive group, the non-responsive group had significantly higher proportions of patients aged ≥ 65 years, with tumor diameter ≥ 5 cm, clinical stage IV disease, and squamous cell carcinoma. Additionally, the non-responsive group exhibited higher carbohydrate antigen 153 (CA153) levels, and lower systemic immune inflammatory nutritional index (SIINI) and lymphocyte to C-reactive protein ratio (LCR) (P < 0.001). Multivariate analysis identified age ≥ 65 years, tumor diameter ≥ 5 cm, stage IV, squamous cell carcinoma, low SIINI, low LCR and high CA153 level as independent factors influencing the efficacy of sintilimab in advanced NSCLC (P < 0.05). The area under the ROC curve of the logistic model established based on these factors was 0.909 (95% CI: 0.875-0.943, P < 0.001). Conclusion Factors including age and tumor diameter can affect the efficacy of sintilimab in the treatment of advanced NSCLC. Clinically, close attention should be paid to conventional clinical features as well as biological indicators, including SIINI, LCR, and CA153, to guide the optimization of treatment strategies.