Background: Programmed death ligand-1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti-programmed cell death protein-1 (PD-1)/anti-PD-L1 therapy in advanced non-small cell lung cancer patients (NSCLC). Immune-related tumor microenvironment (TME) is classified into four different types based on the status of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression. Methods: We retrospectively reviewed advanced NSCLC patients treated with anti-PD-1/anti-PD-L1 therapy between 2015 and 2019, and investigated the association between the efficacy of anti-PD-1/anti-PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, and the density of CD8-positive TILs by immunohistochemistry (/mm²), and mutational profiles assessed by next-generation sequencing. Results: Overall, 228 patients without driver mutation (EGFR, ALK, ROS1, and RET) were included in the analysis. The patients were classified into four following groups: Type I: PD-L1_High (tumor proportion score [TPS]≥50%)/TIL_High (≥85/mm²; n = 73), Type II: PD-L1_Low (TPS < 50%)/TIL_Low ( < 85/mm²; n = 70), Type III: PD-L1_High/TIL_Low (n = 37), and Type IV: PD-L1_Low/TIL_High (n = 48). The progression-free survival (PFS) and objective response rate (ORR) of anti-PD-1/anti-PD-L1 therapy clearly differed according to the different tumor microenvironment (TME) types (ORR and median PFS; Type I: 64%, 14.5 months, Type II: 12%, 2.1 months, Type III: 24%, 3.6 months, Type IV: 41%, 10.8 months). In patients with PD-L1_High tumors, Type I tumors had significantly better ORR and PFS than Type III(ORR: p < 0.001, and PFS: p < 0.001) tumors. Regarding the association between mutational profiles, histology and the TME types, the presence of TP53 mutation and KRAS mutation significantly related to TIL_High (Type I and IV) and PD-L1_High tumors (Type I and III), respectively. Pleomorphic and NSCLC- not otherwise specified histology were associated with Type I tumors, while LCNEC was associated with PD-L1 low tumors (Type II and IV). Conclusions: Various factors (mutational profile and histology) are related to TME classification based on the status of TILs and PD-L1 expression. Differential types of TME, including PD-L1 expression and TILs status, can accurately predict the efficacy of anti-PD-1/anti-PD-L1 therapy.