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Regorafenib, an oral multikinase inhibitor, has shown efficacy in glioblastoma at first recurrence, but its role in later recurrences and in other adult-type diffuse gliomas remains unclear. This multicenter retrospective study aimed to evaluate the safety and efficacy of regorafenib and to identify prognostic factors in patients with adult-type diffuse gliomas, including glioblastoma, who were treated at the second or subsequent recurrences. A total of 68 patients from 22 institutions were analyzed. The median overall survival (OS) was 3.84 months, and the median progression-free survival was 2.46 months. The objective response rate was 13%, and the disease control rate was 48%. Adverse events occurred in 80.9% of patients, most commonly fatigue, anemia, and elevated transaminases. Hand\u2013foot skin reaction (HFSR) of any grade was observed in 36.4% of patients and was associated with significantly improved OS (HR: 0.41; p\u2009=\u20090.005). Regorafenib demonstrated a manageable safety profile and modest activity in this heavily pretreated population. The development of HFSR emerged as a potential prognostic marker for treatment benefit. 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