Abstract: Lung adenocarcinoma (LUAD) is the most common type of lung cancer, which is characterized by strong aggressiveness, rapid progression and strong lethality. It has become an urgent public health problem worldwide. Recent studies have shown that Butyrophilins (BTNs) gene family plays a key role in immune regulation, but its function in LUAD is not yet clear. In this study, the potential of BTN family genes as prognostic biomarkers for LUAD was explored using multi-omics integration and survival analyses. The results showed that the expression levels of butyrophilin gene BTN2A2 and BTNL9 were significantly down-regulated in LUAD (P<0.05), and tightly correlated with the overall survival of patients (P<0.05), respectively. In addition, the expression levels of BTN2A2 and BTNL9 were significantly positively correlated with the infiltration levels of B cells, macrophages and regulatory T cells (P<0.05). The genes co-expressed with BTN2A2 were significantly enriched in T cell activation, cytokine binding, and MHC protein complex binding GO terms, and genes co-expressed with BTNL9 were significantly enriched in cell cycle and DNA replication related GO items (adjust.P<0.05). Therefore, the low expression levels of BTN2A2 and BTNL9 are closely related to the poor overall survival of patients with LUAD, suggesting that they are potential prognostic biomarkers in LUAD patients.