OBJECTIVES: Renal cell carcinoma (RCC) represents 2–3% of all malignancies, and is associated with limited treatment options and low survival rates (median survival for advanced metastatic disease is estimated at 8–12 months). Despite its importance, data on the economic burden of RCC are limited. METHODS: A global, prevalence-based burden-of-illness model was developed and used to estimate the annual, societal economic burden of RCC in selected European countries (UK, Spain, France, and Germany). Key relationships represented in the model include the annual numbers of patients treated for RCC by age group and cancer stage; utilization of cancer-specific treatments; unit costs of these treatments; work-days missed by these patients, and wage rates. Local-area data sources were used to populate the model parameters for each country. Methodological differences across countries resulting from differences in data availability are explained. RESULTS: The annual numbers of cases of RCC include 24,834 in the UK, 3,945 in Spain, 35,714 in France, and 59,864 in Germany. Corresponding estimates of the aggregate annual burden of RCC (€ 2005) are €541 million, €41.8 million, €171 million, and €1.6 billion, respectively (per-patient costs of €21,792, €10,607, €4,781, and €26,397). Healthcare costs account for between 66% and 89% of the burden in each country, with lost productivity accounting for the remainder. Inpatient care for major surgery, radiofrequency ablation, arterial embolization, systemic therapy (chemotherapy, radiation, immunotherapy), and associated complications is the largest driver of healthcare costs, accounting for approximately 80% or more of the burden in each country. Sensitivity analyses indicated that results were most sensitive to assumptions regarding healthcare utilization and unit costs of treatments. CONCLUSION: The economic burden of RCC in Europe is substantial. Interventions to reduce the prevalence of RCC have the potential to yield considerable economic benefits to EU health systems.