Background: Belzutifan, a small molecule HIF-2α inhibitor was FDA approved for the treatment of VHL-associated renal cell carcinoma (RCC), CNS hemangioblastomas and pancreatic NET (pNET). The approval was based on the results from the phase 2, open-label, single-group trial, enrolling 61 patients at approximately 12 study sites (Srinivasan, 2021). Objective responses were seen in 49% patients with VHL associated RCC, 63% patients with VHL-associated CNS hemangioblastomas, and 83% of patients with VHL-associated pNET. Common adverse events included anemia, fatigue, renal dysfunction, nausea, and elevated glucose levels. There is currently very limited data on real-world outcomes using belzutifan in VHL patients. Methods: After obtaining IRB approval, we retrospectively evaluated the efficacy and safety of Belzutifan for patients with VHL disease and renal cell cancer and/or VHL-associated tumors who received Belzutifan between August 2021 and January 2023 at KU Cancer center. Results: A total of 16 patients are started on Belzutifan treatment. The baseline characteristics include median age of 45 years, including 8 (50%) females and 8 (50%) males. Patients with VHL-associated RCCs were seen in 15 patients (n = 15), VHL-associated pNET (n = 13), and CNS hemangioblastomas (n = 13). Patients were started on belzutifan 120mg daily. The patients underwent bloodwork and clinic follow-up every 6-8 weeks, and response assessment was done in 11/15 patients who had follow-up scans at 6-month intervals. Objective Response to Belzutifan in any of these VHL-associated tumors was seen in 9 of 11 patients (81%), and 1/11(9%) had progressive disease (PD). Objective response in patients with VHL-associated RCC was observed in 8/11 (72%) patients and 2/11 (18%) with partial response (PR), and 6/11 (54%) with stable disease (SD). Responses observed in patients with pancreatic lesions were 1/11 patients (9%) with CR, 1/11 (9%) with PR, and 5/11 (45%) with SD. Patients with CNS hemangioblastomas 4/9 (44%) had SD. Safety was assessed in all the patients. The predominant side effect was anemia 12/16 (75%) and fatigue 11/16 (68%). Other side effects reported are fogginess 4/16 (25%), nausea 2/16 (12.5%), dizziness 2/16 (12.5%), and shortness of breath 2/16 (12.5%). Dose reduction to 80mg was needed in 2/16 (12.5%) patients due to moderate fatigue, hypoxia in one, and dysgeusia, respectively. Conclusions: Our real-world outcomes analysis of patients with VHL-associated tumors who are treated with Belzutifan shows an improved objective response when compared to the initial clinical trials, which is promising for patients. The analysis based on our real-world data shows the superior objective response in VHL-associated RCCs with Belzutifan, with a manageable safety profile. These findings reinforce Belzutifan as an effective treatment option for this patient population but warrant confirmation in a larger sample.