Immune-checkpoint signaling plays an important role in immunosuppression of tumors. We aimed to investigate the association of soluble programmed death-ligand 1 (sPD-L1) level in plasma with overall survival (OS) in locally advanced or inoperable nonsmall-cell lung cancer (NSCLC) patients treated with thoracic radiotherapy (TRT). We used ELISA to evaluate the sPD-L1 levels at diagnosis and during TRT in 126 clinically inoperable NSCLC patients. OS rates were followed up and recorded. SPSS software and GraphPad Prism 5 were used for statistics. In this study, the average sPD-L1 levels at baseline, week 2, and week 4 during TRT and post-TRT were 107.2, 51.3, 65.4, and 111.1pg/mL, respectively. Levels of sPD-L1 at week 2 and week 4 were significantly less than at baseline, with both P values<0.001. Using 96.5pg/mL as the cutoff, patients with lower baseline sPD-L1 level had longer OS than those with higher sPD-L1 level (27.8 months vs 15.5 months, P=0.005). Using multivariate analysis, the following factors were significantly associated with longer OS: female, adenocarcinoma, higher TRT dose, and lower baseline sPD-L1 level. Patients with both characteristics of lower baseline sPD-L1 level and higher TRT dose (BED10 >= 84Gy) had the longest OS. To conclude, the lower baseline sPD-L1 level was significantly associated with longer OS in NSCLC patients treated with TRT, which may serve as an independent biomarker and needs further clinical study.