Abstract Structural maintenance of chromosome 2 (SMC2) has been recognized to play an important role in a variety of cancers, but its function in lung adenocarcinoma (LUAD) remains poorly understood.First, we explored the expression level of SMC2 and its relationship with clinical pathological features using the LUAD dataset from the TCGA database. The expression of SMC2 in LUAD cell lines and tissues was verified using quantitative polymerase chain reaction (qPCR). Secondly, Kaplan-Meier analysis, COX regression analysis and Nomogram construction were employed to assess the prognostic potential of SMC2 in LUAD. In addition, the biological behavior and possible signaling pathways of SMC2 were forecasted by protein-protein interaction (PPI) networks, single-gene correlation analysis, genetic ontology (GO) and genome enrichment analysis (GSEA), together with Kyoto Encyclopedia of Genes and Genomes (KEGG). At last, a systematic analysis of crosstalk and mutations between SMC2 and immune features in the tumor microenvironment (TME) was conducted using a single-sample GSEA algorithm, the Tumor Immune Dysfunction and Rejection (TIDE) algorithm, the TIMER 2.0 and TISIDB databases, as well as the cBioportal database.SMC2 was markedly up-regulated in LUAD cell lines and tissues and was strongly correlated with adverse clinicopathological features and prognosis. ROC curves showed a good diagnostic effect (AUC value: 0.787). The enrichment analysis suggested that SMC2 might be involved in the regulation of LUAD cell cycle. The TIMER algorithm and ssGSEA algorithm showed that SMC2 was associated with suppressive immune cells (e.g., B cells) in LUAD. In addition, SMC2 may interact with the expression of molecules such as NDC80, KIFC1, SKA1, NCAPH, ESPL1, MELK, KIF11, SGO1, TOP2A, KNL1, KIF4A, TPX2, TICRR, TTK, KIF14, NCAPG and others to promote LUAD progression. Evidence from the TISIDB database shows that SMC2 is positively associated with immunosuppressive genes such as CD274, PDCD1LG2, TGFBR1 and LAG3. However, it is inversely associated with chemokines and receptors such as CCL14, CCL17, CXCL16, CX3CL1, CX3CR1, CCR6, CCR7 and CXCR5. Also, as predicted by the TIDE algorithm, patients with high SMC2 expression responded poorly to immunotherapy.Our analysis shows that the high expression status of SMC2 in LUAD is associated with poor patient outcomes and describes some potential reasons for this poor prognosis. These findings suggest that SMC2 is associated with the malignant progression of LUAD and therefore may be a potential target for improving outcomes in LUAD in the foreseeable future.