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Abstract: Spatial organization of tumor phenotype is of great interest to radiotherapy target definition and outcome prediction. We characterized tumor phenotype in patients with cancers of the oropharynx through voxel-based correlation of PET images of metabolism, proliferation, and hypoxia. Methods: Patients with oropharyngeal cancer received 18F-fluorodeoxyglucose (FDG) PET/CT, 18F-fluorothymidine (FLT) PET/CT, and 61Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) PET/CT. Images were co-registered and standardized uptake values (SUV) were calculated for all modalities. Voxel-based correlation was evaluated with Pearson’s correlation coefficient in tumor regions. Additionally, sensitivity studies were performed to quantify the effects of image segmentation, registration, noise, and segmentation on R. Results: On average, FDG PET and FLT PET images were most highly correlated (R FDG:FLT =0.76, range 0.53–0.85), while Cu-ATSM PET showed greater heterogeneity in correlation to other tracers (R FDG:Cu-ATSM =0.64, range 0.51–0.79; R FLT:Cu-ATSM =0.61, range 0.21–0.80). Of the tested parameters, correlation was most sensitive to image registration. Misregistration of one voxel lead to ΔR FDG =0.25, ΔR FLT =0.39, and ΔR Cu-ATSM =0.27. Image noise and reconstruction also had quantitative effects on correlation. No significant quantitative differences were found between GTV, expanded GTV, or CTV regions. Conclusions: Voxel-based correlation represents a first step into understanding spatial organization of tumor phenotype. These results have implications for radiotherapy target definition and provide a framework to test outcome prediction based on pretherapy distribution of phenotype. [Copyright &y& Elsevier]