Background: Ripretinib has been proven effective in inhibiting various primary and secondary mutants of KIT/PDGFRA but with limited clinical data. This study is aimed to investigate the efficacy and safety of ripretinib and prognostic predictors based on the current treatment pattern in Chinese patients in a single center. Methods: This retrospective cohort study was based on the prospectively registered database of the First Affiliated Hospital, Sun Yat-sen University. Patients with confirmed recurrent and/or metastatic GIST who received ripretinib as ≥ 2nd line therapy between June 1, 2020, and January 1, 2023 were enrolled. Results: Forty patients receiving ripretinib were enrolled. The median age of the patients was 58.0 years, and the most common primary site of tumor was the small intestine (75.0%). KIT exon 11 (65.0%) was the most common primary mutation, followed by exon 9 (20.0%). Ripretinib was administered as 2^nd- and 3^rd-line therapy in 17.5% of patients, respectively; as 4^th-line therapy in 45% of patients, and as 5^th- or later-line therapy in 20% of patients. Thirty patients who received ripretinib as > = 3^rd-line therapy were eligible for efficacy evaluation. There was no complete remission. Two patients (6.7%) were partial response, and 20 (66.7%) patients were disease stable for at least 8 weeks. The median follow-up time was 18.0 months. The median progression free survival (PFS) (95% confidence interval [CI]) was 5.9 (2.0, 9.7) months, and the median overall survival (OS) was 13.8 (11.5, 16.0) months. In the univariate analysis, patients with a primary mutation in KIT exon 11 (P = 0.002), better ECOG performance status (P = 0.041), and lower tumor burden, including the number (P = 0.016) and cumulative size (P＜0.001) of tumors, had longer PFS. Patients with a primary mutation in KIT exon 11 (P = 0.019), better ECOG performance status (P＜0.001), fewer tumors (P = 0.014), and a younger age (P = 0.039) had longer OS. In the multivariate analysis, the primary mutation (P = 0.004) and the number and cumulative size of tumors (P = 0.024, P = 0.015, respectively) were independent predictors of PFS. The primary mutation (P = 0.025), the number of tumors (P = 0.002), and ECOG performance status (P = 0.002) were independent factors of OS. Ripretinib was generally well tolerated, and no unexpected toxicities were observed. The most common AEs were anemia (45%), alopecia (28%), constipation (25%), and hypoalbuminemia (25%). Grade 3/4 AEs were reported in 25% of patients, and the most common ones were hand-foot syndrome (8%), anemia (5%), and increased aspartate aminotransferase (5%). Conclusions: Ripretinib was safe and effective in Chinese patients with imatinib-resistant GISTs in a real-world setting. Primary KIT exon 11 mutation, lower tumor burden and better performance status were associated with better survival benefit.