Agents targeting vascular endothelial growth factor (VEGF) signaling have been advocated as frontline therapy for advanced renal cancer. The role of interleukin 2 (IL-2) therapy after resistance to VEGF-targeted therapy remains unexplored. We conducted a retrospective analysis of the tolerability and efficacy of IL-2 therapy in patients who had previously received VEGF-targeted therapy. Twenty-three consecutive patients who received salvage IL-2 therapy were analyzed. Fifteen patients had received prior tyrosine kinase inhibitors (TKIs) (sorafenib or sunitinib), whereas 8 patients had received bevacizumab alone. Six of 23 patients did not receive week 2 of cycle 1 of treatment. All 6 of these patients had received prior TKIs. The incidence of severe cardiac toxicities, including 1 sudden cardiac death, in patients receiving prior TKI was 40% (95% confidence interval, 16.3-67.7%), significantly higher than what is expected from historical experience. Only 1 of 23 patients proceeded to receive a second cycle of IL-2. No patients achieved a partial or complete response to therapy. This retrospective analysis highlights unexpected and severe cardiac toxicities in patients receiving IL-2 after VEGF-targeted TKI therapy. The assumption that IL-2 therapy can be safely administered after TKI therapy may not be valid. Further examination of the safety of this sequential approach is necessary and more cautious patient selection seems warranted.