Objective: Pancreatic adenocarcinoma (PAAD) is a malignant digestive tract tumor with a dismal prognosis. The structural maintenance of chromosomes (SMC) gene family plays a role in various of human cancers. However, the function of SMC family members in PAAD remains unclear. This study explores the potential clinical significance of SMC family members in PAAD.Methods: We analyzed the differential expression, prognostic value and methylation levels of SMCs in PAAD patients using R language, Gene Expression Profile Interactive Analysis (GEPIA), University of Alabama Cancer Database (UALCAN). We used Tumor Immune Estimation Resource (TIMER) to assess the correlation between SMC2 and six major tumor-infiltrating immune cells. Immunohistochemistry (IHC) was used to detect the expression of SMC2 in 72 PAAD tissues and 65 adjacent tissues. The relationship between SMC2 and the clinicopathological characteristics and prognosis of PAAD was further analyzed according to the clinical data of the patients.Result: In TCGA (The Cancer Genome Atlas) and GSE16515, GSE15471 datasets, compared to normal tissue, the mRNA and protein expression levels of SMC1A, SMC2, SMC3, SMC4, and SMC6 were higher in PAAD. In addition, increased expression of SMC2 led to a poor prognosis, which could be a potential prognostic biomarker for PAAD patients in TCGA, GSE28735 and GSE21501. Cox univariate and multivariate analysis showed that SMC2 was a prognostic risk factor for PAAD patients in TCGA and GSE21501 dataset. In the 72 PAAD patients of our hospital, the expression level of SMC2 in PAAD tissues was significantly higher than in adjacent tissue, and patients with high expression had a shorter Overall Survival (OS); the expression of SMC2 was related to N stage (P=0.028) and Pathologic stage (P=0.048) of PAAD. Cox univariate and multivariate analysis suggested that SMC2 and N stage were closely related to the prognosis of PAAD patients. Using KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) analysis, we analyzed the gene expression enrichment of SMC2 in biological functions and pathways. Immune infiltration analysis showed that SMC2 was closely associated with B cells, CD8+ T cells, macrophages, neutrophils and dendritic cells. Conclusions: Our study provides a new approach for selecting SMC family prognostic biomarkers in pancreatic cancer. These findings may provide a new direction for diagnosing and treating PAAD in the future.