Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1(+) and CD8(+) tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (P<0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P=0.006), smokers (P=0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (P<0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P=0.054) and expression of EGFR and MET (P<0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P=0.052), and expression of MET (P<0.001) and ERBB2 (P=0.013). The numbers of CD8(+) and programmed cell death-1(+) lymphocytes were higher in smokers (P=0.012 and 0.016) and MET-expressing adenocarcinomas (P<0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1(+)/CD8(+) lymphocytes showed shorter disease-free survival (P=0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.