Background: The aim of this study was to investigate the expression of tumor-derived exosomal RNA eIF4E (exo-eIF4E) in non-small cell lung cancer (NSCLC) and its correlation with prognosis. Material/Methods: The Cancer Genome Atlas (TCGA) data was exacted to investigate the role of tissue eIF4E in NSCLC. We en- rolled 99 NSCLC patients and 40 healthy volunteers with corresponding serum samples in this study. The levels of exo-eIF4E in the peripheral blood of each group were tested by quantitative polymerase chain reaction (PCR). The chi-squared test and the log-rank test were applied to analyze the correlation between the expression levels of exo-eIF4E and the patients' clinical-pathological data, including the overall survival. Results: TCGA data showed that increased eIF4E in NSCLC tissues was associated with late-stage disease (P=0.0497) and inferior overall survival (P=0.017). The expression of exo-eIF4E in the serum of the NSCLC group was significantly higher than that in healthy individuals (P<0.001). Furthermore, advanced TNM stage (P=0.003), distant metastasis (P=0.008), and serum positive cytokeratin fragment 19 (CYFRA21-1) (P=0.023) are more likely present in NSCLC patients with higher exo-eIF4E expression. Moreover, the multivariate combined with univariate analyses verified exo-eIF4E as an independent prognostic factor for shorter overall survival (P=0.01) and progression-free survival (P=0.005). Shorter overall survival (P=0.0005) and inferior progression-free survival (P=0.0017) are more likely present in NSCLC patients with higher exo-eIF4E. Conclusions: Tumor-derived exo-eIF4E in serum can be a practical tool to predict the prognosis of NSCLC.