ABSTRACT: Aim: This retrospective study evaluates whether metastatic sites were associated with progression-free survival (PFS) and overall survival (OS) in patients with renal cell carcinoma treated with targeted therapies. Patients & methods: In total, 358 patients were analyzed. Results & conclusion: After a median follow-up of 56.1 months, median PFS was 11 months and median OS was 24.2 months. Metastatic sites were associated with PFS: lymph nodes (HR: 1.43; 95% CI: 1.12–1.83; p = 0.004), liver (HR: 1.41; 95% CI: 1.05–1.90; p = 0.021), bone (HR: 1.26; 95% CI: 0.96–1.65; p = 0.091), brain (HR: 0.81; 95% CI: 0.46–1.43; p = 0.474) and other sites (HR: 1.07; 95% CI: 0.83–1.38; p = 0.589). Metastatic sites were associated with OS: lymph nodes (HR: 1.73; 95% CI: 1.31–2.29; p < 0.001), liver (HR: 1.71; 95% CI: 1.23–2.37; p = 0.002), bone (HR: 1.48; 95% CI: 1.10–1.98; p = 0.009), brain (HR: 1.21; 95% CI: 0.64–2.28; p = 0.568) and other sites (HR: 1.09; 95% CI: 0.81–1.47; p = 0.568). Patients with >2 metastatic sites had shorter PFS and OS. Every association was lost when introducing the Motzer score in regression models.