PURPOSE: To prospectively compare the accuracy of helical contrast material-enhanced computed tomography (CT) with that of CT and positron emission tomography (PET) combined and CT and single photon emission CT (SPECT) combined in the detection of bone invasion in patients scheduled to undergo surgery for clinically suspected oral cavity carcinoma with possible bone invasion, with surgical results as the reference standard. MATERIALS AND METHODS: This study had local ethical committee approval, and all patients gave written informed consent. Thirty-four consecutive patients (17 men, 17 women; mean age, 64.2 years; age range, 46.0-84.6 years) who were clinically suspected of having bone invasion from oral cavity carcinoma prospectively underwent helical contrast-enhanced CT, coregistered PET/CT, and coregistered SPECT/CT. Two radiologists assessed the contrast-enhanced CT images and two nuclear medicine physicians separately assessed the PET/CT and SPECT/CT images in consensus and without knowledge of the results of other imaging tests. The presence of bone involvement as suggested with an imaging modality was compared with histologic findings in the surgical specimen. RESULTS: With histologic findings as the standard of reference, the accuracy of SPECT/CT (88% [30 of 34 patients]) was lower than that of PET/CT and contrast-enhanced CT (94% [32 of 34 patients] and 97% [33 of 34 patients], respectively). Sensitivity was highest with PET/CT (100% [12 of 12 patients]), and specificity was highest with contrast-enhanced CT (100% [22 of 22 patients]). Fluorine 18 fluorodeoxyglucose (FDG) uptake seen on two sides of the same cortical bone was not a helpful imaging pattern for better identifying bone invasion in patients without evident cortical erosion on CT scans. CONCLUSION: The assessment of cortical erosion with contrast-enhanced CT and the CT information from PET/CT are the most reliable methods for detecting bone invasion in patients with oral cavity carcinoma. FDG uptake seen on PET/CT images does not improve identification of bone infiltration.