ILF2 (NF45) is a sequence-specific DNA binding protein that is involved in mitosis control, transcriptional regulation, DNA breaks repair, microRNA processing and viral replication. In the present study, we aim to investigate the potential role of ILF2 in the progression of non–small cell lung cancer (NSCLC). Western blot analysis indicated that ILF2 was up-regulated in NSCLC tissues, compared with adjacent non-tumorous ones. Furthermore, immunohistochemistry analysis showed that the expression of ILF2 was correlated with histological differentiation, clinical stage and Ki-67 expression in NSCLC specimens. In addition, using Kaplan–Meier survival analysis, we found that high expression of ILF2 predicted poor outcome in NSCLC patients. Furthermore, we showed that up-regulated expression of ILF2 might play a regulatory role in the proliferation of NSCLC cells using serum starvation and release assay. Moreover, knockdown of ILF2 inhibited cell proliferation and cell cycle progress of NSCLC cells. In conclusion, our results indicated that ILF2 was involved in the pathogenesis of NSCLC and might be a potential target for NSCLC therapy.