Programmed cell death ligand 1 (PD-L1) expressed on tumor tissues is a vital molecule for immune suppression and its impact on the response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been reported. The significance of soluble PD-L1 (sPD-L1) for lung cancer patients remains unknown. This study investigated whether sPD-L1 could predict the response of EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR-targeted therapy. We retrospectively evaluated patients who received first-line treatment with EGFR-TKIs for advanced NSCLC with EGFR mutations. Pre-treatment plasma concentrations of PD-L1 and on-treatment (1 month after treatment initiation) plasma concentrations of PD-L1 were measured using the R-plex Human PD-L1 assay. The association between the sPD-L1 level and the clinical outcome was analyzed. Among 66 patients who were eligible for the study, patients with high pre-treatment or on-treatment sPD-L1 levels had decreased objective response rate (ORR) compared with that of patients with low sPD-L1 levels (39.4 vs. 66.7%, p = 0.026 for pre-treatment sPD-L1 level, and 43.5 vs. 73.9%, p = 0.025 for on-treatment sPD-L1 level). A high baseline sPD-L1 level was associated with a shortened progression-free survival (PFS) rate (9.9 vs. 16.1 months, p = 0.005). Both univariate and multivariate analyses showed that a high baseline sPD-L1 level was an independent factor associated with the PFS (hazard ratio [HR] 2.56, p = 0.011). Our study revealed that the sPD-L1 level was strongly related to the outcome of EGFR-TKIs in NSCLC patients harboring EGFR mutations.