Background <p>Duodenal gastrointestinal stromal tumors (GISTs) are rare, and evidence regarding optimal surgical strategy, perioperative imatinib use, and long-term outcomes remains limited. This study evaluated clinicopathologic characteristics, prognostic factors, and survival outcomes in a large single-center cohort, with emphasis on operative strategy.</p> Patients and Methods <p>We retrospectively analyzed 238 patients with duodenal GISTs who underwent surgery between 2000 and 2020 at Zhongshan Hospital, Fudan University. Limited resection (LR) and pancreaticoduodenectomy (PD) were compared. Prognostic factors for recurrence-free survival (RFS) and overall survival (OS) were assessed using Cox regression analyses, and nomograms were constructed to predict 3- and 5-year outcomes.</p> Results <p>Tumors were most commonly located in the second portion of the duodenum. LR was performed in 174 patients and PD in 64, with R0 resection achieved in all cases. PD was associated with longer operative time, greater blood loss, and higher complication rates. Neoadjuvant imatinib facilitated tumor downsizing and enabled LR in selected patients. After a median follow-up of 111 months, 5-year RFS and OS were 88.2% and 97.9%, respectively. Tumor size, mitotic index, epithelioid/mixed morphology, and male sex were independent adverse prognostic factors, while adjuvant imatinib was strongly protective. Surgical type did not affect long-term survival, including for tumors in the second duodenal portion. The nomogram demonstrated good predictive performance.</p> Conclusions <p>When R0 resection is feasible, LR may be a safe and effective surgical option for patients with duodenal GISTs. Surgical strategy should be individualized according to tumor characteristics and anatomical considerations.</p>