PURPOSE: Flexible positron emission tomography (fxPET) employing a non-local means reconstruction algorithm was designed to fit existing magnetic resonance imaging (MRI) systems. We aimed to compare the qualitative and quantitative performance of fxPET among fxPET with MR-based attenuation correction (MRAC), fxPET with CT-based attenuation correction (CTAC) using CT as a part of WB PET/CT, and whole-body (WB) PET/CT. PROCEDURES: Sixteen patients with suspected head and neck cancer underwent 2-deoxy-2-[18F]fluoro-D-glucose WB PET/CT scans, followed by fxPET and 3 T MRI scans. Phantom data were compared among the three datasets. For registration accuracy, we measured the distance between the center of the tumor determined by fxPET and that in MRI. We compared image quality, detection rates, and quantitative values including maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and tumor-to-muscle ratio (TMR) among the three datasets. RESULTS: The phantom data in fxPET, except the percent contrast recoveries of 17-mm and 22-mm hot spheres, were inferior to those in WB PET/CT. The mean registration accuracy was 4.4 mm between fxPET using MRAC and MRI. The image quality was comparable between two fxPET datasets, but significantly inferior to WB PET/CT (p < 0.0001). In contrast, detection rates were comparable among the three datasets. SUVmax was significantly higher, and MTV and TLG were significantly lower in the two fxPET datasets compared with the WB PET/CT dataset (p < 0.005). There were no significant differences in SUVmax, MTV, and TLG between the two fxPET datasets or in TMR among the three datasets. All quantitative values had significantly positive correlations. CONCLUSIONS: Compared with WB PET/CT, the phantom data and image quality were inferior in fxPET. However, the results of the detection rates and quantitative values suggested the clinical feasibility of fxPET.