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Background: Ripretinib, a switch-control kinase inhibitor approved for advanced gastrointestinal stromal tumor (GIST), inhibits primary and secondary KIT and PDGFRA mutations. Real-world data from Western and Middle Eastern populations remain limited. We report outcomes from a molecularly characterized Israeli multicenter cohort. Methods: We conducted a multicenter retrospective cohort study across seven university-affiliated medical centers in Israel. Patients with advanced GIST receiving Ripretinib at any treatment line were eligible. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and response was assessed according to modified RECIST v1.1. Results: Sixteen patients were identified (median age, 67.5 years; 75.0% received Ripretinib in the fourth-line setting). KIT exon 11 mutations were present in 62.5% of patients, including five with secondary resistance mutations involving exon 13 or exons 17/18. Median PFS was 7.0 months (95% CI, 2.0-13.0) and median OS was 14.7 months (95% CI, 4.4-NR). Individual outcomes varied substantially, with PFS ranging from 2.0 to 60.2 months and OS from 2.2 to 60.2 months. Three patients achieved complete responses, with PFS of 20.0, 33.6, and 60.2 months. ORR was 56.3% (CR, n = 3; PR, n = 6) and DCR was 81.3%. No dose reductions or treatment discontinuations due to adverse events were documented; however, adverse events were recorded in only 4 of 16 patients. Conclusions: Ripretinib demonstrated clinical activity in this small, heavily pre-treated cohort. The relatively high ORR and wide variability in outcomes should be interpreted cautiously given the small sample size, retrospective design, and absence of central radiological review. Durable responses were observed in some patients with KIT exon 11 and secondary exon 17/18 mutations, but this exploratory observation does not establish a predictive molecular subgroup. Larger prospective studies with systematic molecular, radiological, and safety assessment are warranted.