Objective: To analyze the expression of soluble programmed death ligand 1 (sPD-L1) in the serum of patients with advanced epidermal growth factor receptor (EGFR) mutated lung adenocarcinoma and to explore its clinical implications. Methods: Seventy-two patients with EGFR mutated advanced lung adenocarcinoma (EGFR mutation group) were included from the Department of Respiratory Diseases in The Second Affiliated Hospital of Soochow University from May 2015 to July 2016. Thirty-one patients with advanced EGFR wild type (WT) lung adenocarcinoma [EGFR WT group, diagnosed via mini specimens from bronchoscopy or transthoracic needle aspiration biopsy (TNAB), matching in sex, age and tumor stage with EGFR mutation group] were also enrolled as controls. The sPD-L1 protein expression in serum was determined by enzyme-linked immunosorbent assay (ELISA) kit. According to the clinical response of two-month EGFR-tyrosine kinase inhibitor (TKI) treatment, all patients were divided into two groups: 36 cases in disease progression groups (PD group) and 36 cases in disease control group (DC group). The sPD-L1 level in peripheral blood between the two groups was analyzed. In EGFR mutation group, the relationship of serum sPD-L1 with TNM staging was analyzed. At the same time, the value of serum sPD-L1 and cancer embryo antigen (CEA) in clinical evaluation of advanced EGFR mutated lung adenocarcinoma was evaluated by analyzing the receiver operating characteristic (ROC) curve. Results: A lower level of sPD-L1 level in EGFR mutation group [0.75(0.15-2.78) μg/L] was found compared with the control group [1.56(0.85-3.29) μg/L] (P<0.001). The expression of sPD-L1 in PD group was significantly higher than that in DC group [1.175(0.62-2.78) μg/L vs 0.625(0.15-2.27) μg/L, P<0.001]. High expression of sPD-L1 in the serum of patients with advanced EGFR mutated lung adenocarcinoma was closely correlated to lymph node metastasis and distant metastasis (χ2=10.985, 4.662; both P<0.05). The area under ROC curve of serum sPD-L1 and CEA was 0.893 (95%CI: 0.830-0.956) and 0.745(95%CI: 0.652-0.839) respectively. Youden index was the maximum when the cutoff value of sPD-L1 was set to 0.815 μg/L, and the sensitivity and specificity were 77.8% and 91.4%, respectively. Conclusions: After EGFR-TKI treatment, the level of sPD-L1 in the serum of patients with advanced EGFR mutated lung adenocarcinoma is lower, which suggests that sPD-L1 expression may depend on the regulation of EGFR signaling pathway. The level of sPD-L1 can reflect the clinical response of EGFR mutated lung adenocarcinoma to EGFR-TKI.