Based on the high expression of carbonic anhydrase IX (CAIX) in 95% of clear cell renal cell carcinoma (ccRCC), the anti-CAIX monoclonal antibody girentuximab can be used for the detection of ccRCC. This clinical study explores the value of Zr-labeled girentuximab positron emission tomography/computed tomography (PET/CT) imaging in diagnostic challenges regarding ccRCC. PET/CT imaging was performed 4 or 5 d after injection of Zr-girentuximab in patients with a primary renal mass (n=16) or a history of ccRCC (n=14). Scans were used for decision making (surgery/active surveillance) in case of indistinct renal masses. All resected PET-positive primary lesions proved to be ccRCC, while no lesion progression was seen in PET-negative masses. In patients suspected of recurrent/metastatic ccRCC, PET/CT with Zr-girentuximab was useful to confirm or exclude ccRCC, evaluate the extent of the disease, and differentiate from other cancers. In this group, Zr-girentuximab PET/CT resulted in a major change in clinical management in five patients (36%), while in three patients (21%) repeat biopsies could be avoided. We conclude that Zr-girentuximab PET/CT is a valuable diagnostic tool that can guide clinical decision making in case of diagnostic dilemmas concerning ccRCC suspicion. Positron emission tomography/computed tomography imaging with Zr-girentuximab can be a valuable diagnostic tool to identify clear cell renal cell carcinoma.