Background <p>Pancreatic ductal adenocarcinoma is a highly aggressive digestive system tumor with a poor prognosis. It is characterized by aggressive features and non-specific early symptoms, often leading to detection only after metastasis has occurred.</p> Objectives <p>To investigate the role of visfatin rs4730153 and omentin-1 rs2274907 gene polymorphisms in susceptibility to pancreatic cancer, while evaluating their serum levels and correlating these levels with clinical, laboratory, and pathological data.</p> Subjects and methods <p>This study involved 192 participants, including 96 native pancreatic cancer patients with confirmed histopathological examinations and 96 age- and gender-matched controls. All individuals underwent a comprehensive medical history assessment, physical examination, and ultrasound imaging. Serum levels of visfatin, omentin-1, and tumor markers were measured using ELISA techniques. Genotyping of visfatin (rs4730153) and omentin (rs2274907) polymorphisms was conducted using quantitative fluorescent PCR.</p> Results <p>The GG genotype and G allele of rs4730153 were significantly more prevalent in the patient group, with odds ratios of 4.154 and 1.711, respectively. Additionally, vascular invasion, poor survival, and a progressive disease course were significantly more common in the AG and GG genotypes. The distribution of omentin-1 rs2274907 indicated that higher serum visfatin levels, larger tumor sizes, vascular invasion, metastasis, poor survival, and lower serum omentin-1 levels were significantly more prevalent in the AT and TT genotypes.</p> Conclusion <p>The visfatin rs4730153 gene polymorphism is associated with susceptibility to pancreatic cancer, vascular invasion, a progressive disease course, and poor survival outcomes. In contrast, the omentin-1 rs2274907 polymorphism is linked to tumor size, vascular invasion, metastasis, and overall survival.</p>