Background Immunotherapy has achieved good therapeutic effects in non-small cell lung cancer (NSCLC) patients. However, in order to realize individualized and precise treatment, it is urgent to find effective biomarkers associated with the therapeutic effect.Objective To detect the level of blood tumor mutational burden (bTMB) in patients with NSCLC and explore its correlation with the efficacy of immunotherapy, in order to provide reference for clinical evaluation of the effect of immunotherapy.Methods Clinical data about 155 patients who were clearly diagnosed with NSCLC by pathology (percutaneous transluminal biopsy, bronchoscopic biopsy, etc.) at the Third Medical Center of Chinese PLA General Hospital were retrospectively analyzed, and all of them underwent second-generation sequencing (next generation sequencing, NGS) with negative driver genes, and received either immunomodal therapy or immunocombination therapy. A Logistic regression model was used to analyze the influence of variables such as bTMB on the short-term therapeutic effect. The Kaplan-Meier survival analysis was employed to study the progression-free survival (PFS) and overall survival (OS) of the patients.Results Among the 155 patients, 116 cases were male (74.84%). The median age was 69 (ranging from 59 to 74) years, and the median bTMB was 11.45 (7.23, 14.45) mut/Mb. Among the 155 patients, no patient achieved complete response (CR). There were 25 patients with progress disease (PD), accounting for 16.13%, 34 patients with stable disease (SD), accounting for 21.93%, and 96 patients with partial response (PR), accounting for 61.94%. Significant differences in bTMB levels were observed among patients with different treatment responses (P＜0.001): PR patients demonstrated the highest median bTMB (12.43 mut/Mb, IQR: 9.65-15.48), followed by SD patients (11.45 mut/Mb, IQR: 6.95-14.31), while PD patients showed the lowest levels (5.97 mut/Mb, IQR: 4.78-7.75). Logistic regression analysis confirmed a positive correlation between bTMB levels and immunotherapy efficacy in NSCLC patients (OR: 1.213, 95%CI: 1.124-1.314, P＜ 0.001). When stratified by the median bTMB of 11.45 mut/Mb, the high-bTMB group exhibited significantly longer median progression-free survival compared to the low-bTMB group (12.00 months vs 8.2 months, HR: 0.450, 95%CI: 0.300-0.675, P＜ 0.001).Conclusion bTMB expression levels can influence the efficacy of immunotherapy in NSCLC and are expected to become a routine predictive biomarker for NSCLC immunotherapy.