Background and Aim. Myeloid-derived suppressor cells (MDSCs) contribute to the process of malignant transformation and tumor progression through immuno- and nonimmunosuppressive mechanisms. The current study is aimed at providing the predictive and prognostic role of Mo-MDSCs in advanced non-small-cell lung cancer (NSCLC) in relation to different hematologic indices. Methods. We recruited 40 cases of advanced NSCLC, stages III and IV, aged > 18 – < 70 years old, and eligible to receive chemotherapy with or without radiotherapy, along with 20 healthy controls of comparable age and sex; after diagnosis and staging of patients, blood samples were collected for flow cytometric detection of Mo-MDSCs. Results. Significant accumulation of Mo-MDSCs in patients compared to their controls ( p < 0.0001 ). Furthermore, these cells accumulated significantly in stage IV compared to stage III ( p = 0.006 ) and correlated negatively with overall survival ( r = − 0.471 , p = 0.002 ), lymphocyte to monocyte ratio ( r = − 0.446 , p = 0.004 ), and mean platelet volume to platelet count ratio (MPV/PC) ( r = − 0.464 , p = 0.003 ), patients with Mo ‐ MDSCs < 13 % had significantly better survival than those with Mo ‐ MDSCs ≥ 13 % ( p = 0.041 ). Conclusion. Mo-MDSCs represent one of the key mechanisms in the immunosuppressive tumor microenvironment (TME) to play major roles not only in the carcinogenesis of lung cancer but also in disease progression and prognosis and, in addition, predict the efficacy of immune checkpoint inhibitors; our results provided some support to target Mo-MDSCs and needed to be augmented by further studies.