Background Tumor perfusion may inform therapeutic response and resistance in metastatic renal cell carcinoma (RCC) treated with antiangiogenic therapy. Purpose To determine if arterial spin labeled (ASL) MRI perfusion changes are associated with tumor response and disease progression in metastatic RCC treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Materials and Methods In this prospective study (ClinicalTrials.gov identifier: NCT00749320), metastatic RCC perfusion was measured with ASL MRI before and during sunitinib or pazopanib therapy between October 2008 and March 2014. Objective response rate (ORR) and progression-free survival (PFS) were calculated. Perfusion was compared between responders and nonresponders at baseline, at week 2, after cycle 2 (12 weeks), after cycle 4 (24 weeks), and at disease progression and compared with the ORR by using the Wilcoxon rank sum test and with PFS by using the log-rank test. Results Seventeen participants received sunitinib (mean age, 59 years ± 7.0 [standard deviation]; 11 men); 11 participants received pazopanib (mean age, 63 years ± 6.6; eight men). Responders had higher baseline tumor perfusion than nonresponders (mean, 404 mL/100 g/min ± 213 vs 199 mL/100 g/min ± 136; P = .02). Perfusion decreased from baseline to week 2 (-53 mL/100 g/min ± 31; P < .001), after cycle 2 (-65 mL/100 g/min ± 25; P < .001), and after cycle 4 (-79 mL/100 g/min ± 15; P = .008). Interval reduction in perfusion at those three time points was not associated with ORR (P = .63, .29, and .27, respectively) or PFS (P = .28, .27, and .32). Perfusion increased from cycle 4 to disease progression (51% ± 11; P < .001). Conclusion Arterial spin labeled perfusion MRI may assist in identifying responders to vascular endothelial growth factor receptor tyrosine kinase inhibitors and may help detect early evidence of disease progression in patients with metastatic renal cell carcinoma. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Goh and De Vita in this issue.