Background: The combination of cabozantinib plus nivolumab (Cabo + Nivo) was approved in Europe in 2021 for the first-line (1L) treatment of patients with advanced renal cell carcinoma (aRCC) based on evidence from the phase 3 CheckMate 9ER trial. In the CheckMate 9ER trial (N = 651), Cabo + Nivo improved overall survival (hazard ratio [HR] 0.70 [95% confidence interval: 0.55–0.90]; p = 0.0043) and progression-free survival (HR 0.56 [95% CI: 0.46–0.68]; p≤ 0.0001) versus sunitinib. There is clinical interest in the effectiveness and tolerability of Cabo + Nivo as used in routine cancer care. Methods: CaboCombo is a prospective, international, real-world non-interventional study to evaluate the effectiveness and tolerability of 1L Cabo + Nivo in adults (aged ≥ 18 years) with aRCC with a clear-cell component. In total 311 patients will be enrolled across 70 centers in countries where 1L Cabo + Nivo has marketing authorization and reimbursement. The decision to prescribe Cabo + Nivo will be made prior to, and independently from, the decision to enroll patients. The primary endpoint is real-world landmark overall survival assessed 18 months after Cabo + Nivo initiation. Secondary endpoints include: real-world treatment patterns; median progression-free survival; objective response rate; duration of response; disease control rate; time to response; treatment-emergent adverse events, and changes in disease-related symptoms and pain during the treatment period (assessed by the Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index – Disease Related Symptoms questionnaire, and the Numerical Pain Rating Scale). Patients will be enrolled over 24 months and followed for up to 42 months. The nature and timing of study visits and assessments will be as per usual care at each participating center; no additional diagnostic or monitoring procedures will be conducted. Treatment will continue until disease progression, unacceptable toxicity or withdrawal of participant consent. Two interim analyses will be conducted, the first a description of baseline characteristics when at least 50% of participants have been recruited. No changes in study design or conduct will be made based on the results of these analyses. Clinical trial information: NCT05361434.