Background and Aims ATP-binding cassette transporter A5 (ABCA5), a member of the ABC transporter, plays a crucial role in various cancers. However, the role of ABCA5 in pancreatic cancer remains unclear. Therefore, this study was conducted to explore the expression of ABCA5 in pancreatic cancer and its relationship with prognosis of patients, using both bioinformatics analysis and clinical sample validation. Additionally, the potential mechanisms of ABCA5 in pancreatic cancer were analyzed.Methods The expression of ABCA5 in pancreatic cancer tissues and normal tissues was analyzed using TCGA and GEO databases. Kaplan-Meier survival curves and Cox proportional hazards models were used for univariate and multivariate analyses of the survival of patients. Immunohistochemistry was employed to detect ABCA5 expression in 65 pancreatic cancer and adjacent tissue samples, and its association with prognosis and clinicopathologic features was assessed. TIMER, STRING, and Gene MANIA databases were used to analyze ABCA5 in relation to immune cell infiltration, protein-protein interaction networks (PPI), and gene-gene interaction networks. Gene set enrichment analysis (GSEA) and correlation analysis were performed to explore the potential signaling pathways and mechanisms involving ABCA5 in pancreatic cancer. The relationship between ABCA5 and drug sensitivity was analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC).Results In both TCGA and GEO datasets, ABCA5 expression was significantly lower in pancreatic cancer tissues compared to normal tissues (both P<0.05); patients with low ABCA5 expression had significantly shorter overall survival in both TCGA and GSE62452 datasets (both P<0.05); ABCA5 expression was identified as an independent prognostic factor for pancreatic cancer patients (HR=0.458, P=0.001; HR=0.439, P=0.017). Clinical analysis of 65 cases revealed that ABCA5 was downregulated in cancer tissues compared to adjacent tissues, and patients with low ABCA5 expression had worse prognoses (both P<0.05). Univariate and multivariate Cox regression analyses indicated that ABCA5 expression was an independent prognostic factor for pancreatic cancer patients (HR=0.327, P=0.032). TIMER database results showed a close association between ABCA5 expression and immune infiltration. The PPI network revealed 14 interacting proteins associated with ABCA5, while the gene-gene interaction network identified 20 interacting genes. Gene enrichment and correlation analyses suggested that ABCA5 may be related to the cell cycle and ferroptosis in pancreatic cancer. Patients with high ABCA5 expression showed significantly lower IC₅₀ values for five therapeutic drugs than those with low ABCA5 expression (all P<0.05).Conclusion The expression of ABCA5 is downregulated in pancreatic cancer tissue and is associated with poor prognosis in patients. ABCA5 expression is an independent prognostic factor for pancreatic cancer, and its potential mechanism in pancreatic cancer may involve the cell cycle, immune regulation, and ferroptosis.