Introduction <p>A variety of surgical options are available to achieve a complete oncological resection for duodenal gastrointestinal stromal tumours (GISTs). The most common location of such tumours is the second portion (D2) of the duodenum. The key step in assessing the feasibility of localised duodenal resection is the relationship between the GIST and ampulla. We present our surgical approach and results for patients with D2 GISTs undergoing surgical resection at our tertiary oncology centre.</p> Methods <p>Patients diagnosed with duodenal GIST involving D2 who underwent surgical resection at The Royal Marsden NHS Foundation Trust between March 2018 and May 2024 were included in this study.</p> Results <p>11 patients with D2 GISTs were included in the study. The mean age was 60 ± 11.2&#xa0;years. The majority (<i>n</i> = 9) of patients presented with gastrointestinal haemorrhage. The locations of duodenal GIST were D1/2 (<i>n</i> = 1), D2 (<i>n</i> = 8), and D2/3 (<i>n</i> = 2). 9 patients received neoadjuvant Imatinib treatment. 10 patients had peri-ampullary D2 GISTs resected with pancreatic preservation. There were no anastomotic or duodenotomy leaks. One patient developed delayed gastric emptying (DGE). One patient who underwent segmental D2/3 resection and duodeno-jejunostomy developed biliary obstruction and required PTC and biliary stent. One patient who presented with biliary obstruction underwent pancreaticoduodenectomy developed a Grade A post-operative pancreatic fistula. The median study follow-up was 38&#xa0;months (range 3–72&#xa0;months) and at the end of the study period only one patient had developed recurrence. All patients remain disease free and under active follow-up.</p> Conclusion <p>In summary, we demonstrate that for D2 GISTs presenting without biliary obstruction, localised D2 resection should be considered, and this approach is associated with low patient morbidity and good long-term patient outcomes.</p>