Background <p>Surgical resection is recommended for intraductal papillary mucinous neoplasms (IPMN) with high-risk stigmata (HRS). However, in clinical practice, some patients are managed conservatively because of their advanced age or comorbidities. We aimed to evaluate the clinical course and identify risk factors for malignant progression in patients with HRS-positive IPMN.</p> Patients and Methods <p>We retrospectively analyzed 100 consecutive patients with HRS-positive IPMN treated at a single tertiary center between 2015 and 2024. Patients were classified into a surgical group (<i>n</i> = 63) and an observation group (<i>n</i> = 37). Malignant progression was defined as pathologically confirmed invasive carcinoma in resected specimens or as clinical progression in the observation cohort. Logistic regression analysis was performed to identify factors associated with malignant progression.</p> Results <p>Malignant progression occurred in 18 patients (18%), including 13 with invasive carcinoma in the surgical group and 5 with clinical progression in the observation group. The median time to progression was 12 months (range 1–83 months). In multivariate analysis, carbohydrate antigen 19-9 (CA19-9) &gt; 37 U/mL (odds ratio [OR] 5.6, 95% confidence interval [CI] 1.5–20.7, <i>p</i> = 0.0097) and fluorodeoxyglucose (FDG) uptake with a standardized uptake value (SUV) &gt; 3 on positron emission tomography-computed tomography scan (PET-CT) (OR 4.7, 95% CI 1.3–17.1, <i>p</i> = 0.0189) were independently associated with malignant progression, whereas enhancing mural nodules ≥ 5 mm were not statistically significant.</p> Conclusions <p>In patients with HRS-positive IPMN, malignant progression was associated with tumor biological and metabolic markers rather than with morphologic criteria alone. Risk-adapted decision-making incorporating CA19-9 and FDG-PET findings may help refine patient selection and avoid unnecessary surgery in selected high-risk patients.</p>