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In this retrospective study, patients with von Hippel-Lindau disease-associated renal cell carcinoma (VHL-RCC) were identified from insurance claims data and were found to have $36,450 higher annual healthcare costs than patients without VHL disease or RCC. This study underscores the importance of treatments that can reduce the clinical burden and medical intervention costs of VHL-RCC. Introduction: We developed a claims-based algorithm to identify patients with von Hippel-Lindau disease-associated renal cell carcinoma (VHL-RCC) from a real-world database and quantified the prevalence, healthcare resource utilization (HRU), and healthcare costs of VHL-RCC in the United States (US). Methods: Using data from the Optum Clinformatics Data Mart (2007-2020), an algorithm was developed to identify patients with VHL-RCC, who were matched to controls without VHL disease or RCC. VHL-RCC prevalence in 2019 was estimated and standardized to the US population. HRU and costs were compared between patients with VHL-RCC versus controls, and costs associated with tumor reduction procedures were estimated among patients with VHL-RCC. All costs were adjusted to 2020 US dollars. Results: VHL-RCC prevalence in the US was 0.92 per 100,000 persons, resulting in 3023 estimated patients with VHL-RCC in the US. The VHL-RCC cohort (N = 160) incurred higher rates of inpatient, outpatient, and emergency department visits versus controls (N = 800), translating to $36,450 more in adjusted all-cause annual healthcare costs. By examining only claims with an associated RCC diagnosis, it was estimated that patients with VHL-RCC incurred $21,123 annually in healthcare costs due to RCC management, and the average cost of nephrectomy was $29,313. Among different complications of RCC-related tumor reduction procedures, end-stage renal disease was the costliest, which incurred $65,338 over 6 months postnephrectomy. Conclusion: VHL-RCC was associated with significant HRU and healthcare costs, including those related to tumor surgeries. This study underscores the importance of novel therapies that can reduce the clinical burden and medical intervention costs of VHL-RCC. [ABSTRACT FROM AUTHOR]