Purpose <p>Multiple gastrointestinal stromal tumors (MGISTs) are relatively rare and may exhibit distinct clinical characteristics and prognosis compared to solitary GISTs (SGISTs). The objective of this study was to investigate the clinical features and prognosis of MGISTs.</p> Materials and methods <p>The Surveillance, Epidemiology, and End Results (SEER) database was used to identify all GIST patients diagnosed between 2010 and 2019. Multiple imputation (MI) was utilized to address missing data, while propensity score matching (PSM) was conducted to mitigate selection bias. The impact of demographic and clinical factors on overall survival (OS) was evaluated using Kaplan–Meier analyses and Cox proportional hazards models.</p> Results <p>A total of 6241 patients were included in the study, with 4546 having SGISTs and 1695 having MGISTs. MGISTs have a higher prevalence in males, Caucasians, and elderly patients. Compared to MGISTs, the OS of SGISTs is significantly better (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.44–0.55, <i>P</i> &lt; 0.001). After PSM, 3390 patients (equally distributed between the SGISTs and MGISTs groups) were matched for comparison. The OS of SGISTs is still better than that of MGISTs (HR 0.65, 95% CI 0.56–0.75, <i>P</i> &lt; 0.001). Age, sex, site, surgery, marital status, mitotic rate, and chemotherapy were independent risk factors for OS in MGISTs patients. The OS of MGISTs patients who underwent surgery was significantly better than those who did not (<i>P</i> &lt; 0.001). Similarly, chemotherapy-treated MGISTs patients showed improved OS compared to those who did not receive it (<i>P</i> = 0.045).</p> Conclusions <p>MGISTs have unique clinical characteristics and show worse OS compared to SGISTs. Surgical intervention and chemotherapy has the potential to ameliorate the prognosis of patients with MGISTs.</p>