The multicentre, randomized, phase III trial TiNivo-2 was conducted to assess the efficacy of the vascular endothelial growth factor receptor inhibitor tivozanib alone versus in combination with the immune checkpoint inhibitor (ICI) nivolumab in patients with advanced renal cell carcinoma (RCC) who had progressed during or after 1–2 previous lines of therapy including one ICI. Progression-free survival (PFS) was higher in patients in the monotherapy group (7.4 months) than in patients receiving combination therapy (5.7 months; HR 1.10, 95% CI 0.84–1.43; P = 0.49). These results show that re-challenging patients with advanced RCC with ICI therapy is not advisable and suggest tivozanib monotherapy as a viable treatment option in the post-ICI setting.