Background: Carbonic anhydrase IX (CAIX), a transmembrane glycoprotein with an intracellular enzymatic domain, is overexpressed in ccRCC as a result of VHL loss. Chimeric antibody girentuximab is a monoclonal antibody that binds an extracellular epitope of CAIX. Iodine radiolabeled (I-124) girentuximab can be used as a PET radiotracer and has been shown to identify ccRCC primary tumors with high sensitivity and specificity. This study was designed to test the feasibility of using I-124 girentuximab PET/CT in the m ccRCC setting and to produce preliminary data regarding the operating characteristics of these scans in m ccRCC. Methods: Patients (pts) with ccRCC refractory to standard antiangiogenic therapy were treated with brivanib (Bristol-Myers Squibb, Co.), a tyrosine kinase inhibitor of VEGFR2 and FGFR. Baseline I-124 girentuximab scans were obtained. For 1 pt, a second scan was performed after 8 weeks. Clinical outcome was measured radiographically by RECIST 1.0 and standard cross-sectional imaging. Results: 5 pts had 6 I-124 girentuximab PET/CT scans. No adverse events occurred. 17 RECIST target lesions were identified at baseline. PET showed heterogeneous expression of CAIX in all scans: overall, 9 of 17 (53%) metastatic target lesions expressed CAIX. Progressive disease occurred in 5/6 pts within 4 months on treatment, and progression occurred in all 8 of the CAIX non-avid lesions (100%) in these pts. One pt achieved a RECIST partial response (PR) with treatment – the pt for whom paired studies were obtained. For this pt, a PET PR was observed 2 cycles earlier than with conventional imaging. Conclusions: I-124 girentuximab PET/CT was safe and feasible in m ccRCC. We found that metastases were detected. More importantly, for pts with ccRCC refractory to conventional antiangiogenic therapies, CAIX expression was heterogeneous, and progression occurred in CAIX non-avid lesions. Taken together, these data suggest that CAIX expression identified with this functional imaging modality represents a biological prerequisite for continued antiangiogenic therapeutic activity, and the heterogeneous CAIX expression observed helps to explain why brivanib was not useful in this setting. Clinical trial information: NCT01253668.