Background <p>Gastrointestinal stromal tumors (GISTs) are a rare and less well-characterized disease. There is limited information on the clinical features of small intestinal GISTs at different sites.</p> Aims <p>To enhance the understanding of the clinical characteristics and disease behavior of small intestinal GISTs based on their sites.</p> Methods <p>We conducted a retrospective review of medical records for 317 patients diagnosed with primary small intestinal GISTs confirmed by surgical pathology, comparing their clinical features and tumor characteristics.</p> Results <p>According to this cohort’s data, duodenal GISTs presented with longer disease durations and higher prevalence of melena (44.6%), while jejunal GISTs manifested as abdominal masses (11.5%) and acute gastrointestinal bleeding (GIB) (13.3%), with the highest rate of emergency surgeries (16.8%). Ileal GISTs were associated with an older age of onset and a higher prevalence of hematochezia (19.6%), with one-third of cases discovered incidentally during gynecological procedures. Notably, the biological behavior of small intestinal GISTs varied significantly by sites. Tumors demonstrated different immunochemical markers and a progressive increase in diameter, mitotic activity, T and M stages, and risk classification from the duodenum to the jejunum and ileum. These findings warrant further validation in prospective multicenter studies.</p> Conclusions <p>Small intestinal GISTs might exhibit distinct clinical presentations and oncological features depending on their sites.</p> Visual abstract <p></p>