Background <p>Emerging evidence implicates sialic acid-binding immunoglobulin-like lectin (SIGLEC) family members as emerging immune checkpoints and as having a role in cancer progression. However, as a relatively unique SIGLEC member, SIGLEC12 has rarely been studied in cancer, and its clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains largely unknown. This study aimed to investigate the expression pattern and prognostic value of SIGLEC12 in PDAC.</p> Methods <p>A retrospective cohort of 145 patients with PDAC was enrolled. SIGLEC12 expression was assessed by immunohistochemistry on tumor microarrays. The association between SIGLEC12 and overall survival (OS) and recurrence-free survival (RFS) was evaluated using the Kaplan–Meier method and Cox regression analysis. The potential effect modification of SIGLEC12 was assessed by interaction analyses.</p> Results <p>SIGLEC12 expression was significantly upregulated in PDAC tissues at both protein and messenger RNA levels (<i>P </i>&lt; 0.001). High SIGLEC12 expression was associated with poorer OS and RFS and was an independent prognostic factor (OS: hazard ratio [HR] 1.928, <i>P </i>= 0.0004; RFS: HR 1.569, <i>P </i>= 0.022). Interaction analyses revealed that the prognostic effects of carbohydrate antigen 19-9 (CA19‑9) and adjuvant chemotherapy (ACT) were significantly modified by SIGLEC12. Notably, elevated CA19-9 predicted poorer survival, and ACT improved survival only in patients with low SIGLEC12 expression and not in those with high SIGLEC12 expression.</p> Conclusions <p>SIGLEC12 is frequently upregulated in PDAC and predicts poor prognosis. Notably, our exploratory findings suggest that SIGLEC12 may modify the prognostic effect of CA19‑9 and the therapeutic benefit of ACT. These findings position SIGLEC12 as a promising prognostic biomarker and novel therapeutic target in PDAC, with potential for further roles in refining risk stratification and guiding personalized treatment decisions.</p>