Interleukin-36α, a newly recognized IL-1 family member, has been previously reported to play a pivotal role in autoimmunity diseases and acute inflammatory reactions. Recently, several studies have indicated that IL-36α has potential anti-cancer effects against certain types of cancer. However, the expression pattern and functional role of IL-36α in non-small cell lung cancer (NSCLC) have not been elucidated. Here, we report that the mRNA and protein levels of IL-36α are significantly reduced in NSCLC tissues. Low levels of intratumoral IL-36α are correlated with higher tumor status, advanced TNM stage, increased vascular invasion, and shorter overall survival (OS). Intratumoral IL-36α expression is an independent prognostic factor for OS (hazard ratio = 3.081; P = 0.012) in NSCLC patients. Overexpression of IL-36α in lung cancer cells did not disturb cell proliferation, apoptosis, or cell cycle distribution in vitro, but markedly inhibited tumor growth in vivo. Mechanistically, IL-36α reduced the expression and secretion of vascular endothelial growth factor A (VEGFA) through inhibiting HIF-1α expression. Finally, decreased IL-36α expression was associated with high MVD and VEGFA in NSCLC patients. Together, our findings suggest that IL-36α expression is a valuable marker indicating poor prognosis in NSCLC patients. This article is protected by copyright. All rights reserved.