OBJECTIVE: We investigated the relationship between 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET using volume-based parameters and epidermal growth factor receptor (EGFR) mutation status, programmed death-ligand-1 (PD-L1) expression level, and their combination, in pretreated non-small cell lung cancer (NSCLC). METHODS: FDG PET findings and EGFR mutation status and PD-L1 expression level were investigated retrospectively in 93 patients with newly diagnosed NSCLC (77 adenocarcinomas, 16 squamous cell carcinomas). Tumors were divided into six groups: EGFR mutant/negative PD-L1, EGFR mutant/low PD-L1, EGFR mutant/high PD-L1, EGFR wild/negative PD-L1, EGFR wild/low PD-L1, and EGFR wild/high PD-L1. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for primary tumor were measured from PET images. The EGFR mutation status and PD-L1 expression level were estimated in tumor tissue specimens and compared with the PET parameters. RESULTS: None of the PET parameters differed significantly between EGFR-mutated and wild-type EGFR. According to the PD-L1 level, significant differences were detected in SUVmax (P = 0.001) and TLG (P = 0.016), but not MTV. Comparing all six groups, significant difference was detected in only SUVmax (P = 0.011). CONCLUSION: Based on the preliminary results of this study, FDG PET may help in the prediction of PD-L1 expression level, but not EGFR mutation status, in patients with newly diagnosed NSCLC. The SUVmax rather than MTV or TLG, may be of value in predicting the six groups according to the combination of EGFR mutation status and PD-L1 expression level.