Objective: The objective of this study is to investigate the relationship between programmed cell death ligand 1 (PD-L1) expression and the mutation status of epidermal growth factor receptor (EGFR) in lung adenocarcinoma, as well as the correlation between the clinical features of patients and mRNA levels of PD-L1 and components of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/phosphatase and tensin homolog (PTEN) pathways. Methods: mRNA levels of PD-L1, PI3K, AKT, and PTEN in tumor and matched normal tissues of patients with EGFR mutation-positive lung adenocarcinoma were determined by real-time polymerase chain reaction. Results: Twenty-three patients with EGFR mutation-positive lung adenocarcinoma were enrolled, and 46 samples (23 pairs of tumor and matched normal lung tissues) were collected. PD-L1 and AKT mRNA levels were higher in EGFR mutation-positive lung adenocarcinoma than in matched normal lung tissues (P = 0.047 and P = 0.046, respectively), whereas PI3K and PTEN mRNA levels were significantly lower in the cancerous tissues (P = 0.009 and P = 0.039, respectively). PD-L1 expression was positively correlated with PI3K/AKT signaling pathway activation. PD-L1 upregulation in lung adenocarcinoma was positively correlated with EGFR exon 19 mutations (P = 0.034). AKT mRNA upregulation was correlated with lymph node metastasis (P = 0.034). PTEN mRNA downregulation was correlated with high tumor staging and lymph node metastasis (P = 0.035 and P = 0.014, respectively). Conclusion: Elevated PD-L1 mRNA expression in lung adenocarcinoma is associated with EGFR mutation and may be mediated through the PI3K-AKT pathway. EGFR exon 19 mutations closely correlate with increased PD-L1 mRNA expression. Increased AKT mRNA expression correlates with lymph node metastasis, while decreased PTEN mRNA levels correlate with advanced tumor stage and lymph node metastasis.