425 Background: The prevalence of intratumoral genetic heterogeneity in renal cell carcinoma (RCC) has recently been elucidated, and the clinical implications are currently under investigation. The effects of neoadjuvant pazopanib on intratumoral genetic heterogeneity in RCC are unknown. Methods: With IRB approval and informed consent, 5 patients with clinically localized clear cell RCC were treated with pazopanib chemotherapy for ≥8 weeks prior to radical nephrectomy. Prior to treatment, the tumors were sampled by percutaneous core biopsy for histologic and genetic analysis. Peripheral leukocytes were collected for wild-type genetic analysis. Following nephrectomy, tumors were sampled for histologic and genetic analysis. DNA was extracted from all samples and ultra-deep multiregion exome genetic sequencing was performed to identify genetic mutations. Mutant allele frequencies were calculated and compared between pre- and post-pazopanib samples. Hierarchical cluster analysis was performed to evaluate intra- and inter-tumoral heterogeneity, and the fraction of private mutations was tabulated to evaluate change in clonality after pazopanib treatment. Results: Patients age ranged from 52 to 75, and tumors ranged from T2 to T4 (all cN0M0). Percent change of tumor volume after treatment ranged from -10% to -33%. Hierarchical cluster analysis of genetic mutations revealed that all pre- and post-pazopanib sample pairs clustered more closely with each other than with the other tumors, suggesting that intertumoral heterogeneity overshadowed intratumoral heterogeneity. Important genetic mutations in RCC (such as VHL, PBRM1, and SETD2) were highly represented in our dataset, thus validating our approach. After pazopanib, total numbers of mutations as well as the fraction of private mutations decreased in all tumors, showing an increased clonality with pazopanib therapy. Conclusions: RCC is highly genetically heterogeneous. However, this heterogeneity decreases with neoadjuvant pazopanib. These data have implications for the accuracy of percutaneous biopsy to predict tumor biology, and begin to reveal insights into the biologic and genetic response of these tumors to pazopanib.