Background: Response assessment is critical in evaluating effectiveness of anticancer treatment. Tyrosine kinase inhibitors (TKIs) in renal cell carcinoma (RCC) are associated with significant clinical benefit but may not result in significant tumour size reduction. Thus standard size-based response assessment with RECIST is insensitive, resulting in low response rates which do not reflect disease control measured by time to progression. We compared the use of combined size and density response criteria with standard size based criteria in metastatic RCC patients treated with TKI's. Patients and methods: CT scans from 32 patients with metastatic RCC treated with either sunitinib (18) or cediranib (14) were assessed. 12 patients were excluded from the analysis as 10 had non-contrast enhanced scans due to renal impairment and 2 stopped treatment due to toxicity. Scans from 20 evaluable patients at baseline and 12 weeks on treatment were assessed using RECIST, Choi, and modified criteria in which both a 10% decrease in size and 15% decrease in density were required to define a partial response (PR). Response assessment performed using each of the three methods was compared with time to disease progression (TTP) defined by RECIST using Kaplan-Meier statistics and Log-rank test with significance at 5%. Results: Partial response (PR) and stable disease (SD) defined by modified criteria successfully identified patients with a long TTP (448 days) or short TTP (89 days) respectively (p=0.002). Neither RECIST nor standard Choi criteria successfully discriminated between patients having a short or long clinical benefit. Conclusion: A combined reduction in both size and arterial phase density of RCC metastases treated with TKIs correlates with TTP. RECIST and standard Choi criteria appear inferior.