Background: Pancreatic adenocarcinoma (PAAD) is one of the most aggressive malignancies with a very poor prognosis. Exploring more therapeutic targets and prognostic biomarkers is of great significance to improve the prognosis of PAAD patients. Increasing evidence supports that the speckled protein (SP) 100 family is associated with human cancer and immune disorders. However, the function of the SP100 family members in PAAD is still unclear.Methods: R, Cytoscape, cBioPortal, and other software and online databases were used to comprehensively analyze the expression characteristics, prognostic value, and oncogenic mechanism of the SP100 family in PAAD.Results: The high expression of SP100 family members in PAAD was significantly correlated with poor clinicopathological features and poor prognosis of PAAD patients. Mechanistically, TP53 mutations were significantly associated with the expression levels of the SP100 family members, which were significantly coexpressed with M6A methylation regulators and were activated in multiple oncogenic pathways, including the EMT pathways. Moreover, we found that their expression levels were significantly correlated with the sensitivity of multiple traditional chemotherapeutic drugs.Conclusion: The SP100 family is closely related to the occurrence and development of PAAD and can be used as a new biomarker and therapeutic target for patients with PAAD.