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Positron emission tomography (PET) [ 15O] activation studies have benefited significantly from three-dimensional (3-D) data acquisition. However, they have been slow to take advantage of new 3-D reconstruction techniques. Compared with the widely used 3-D reprojection reconstruction (3DRP), the advantage of signal and noise for iterative algorithms has been outweighed by concern about long and complicated reconstruction procedures and inconsistent performance. Most pseudo-3-D algorithms, such as rebinning methods, aim at increasing the speed of reconstruction but lack further resolution improvement or noise control. Although many evaluations have been conducted through simulations and phantom experiments, the spatially varying nature of signal and noise and the complexity of biological effects have complicated the interpretation of real data based on simulation or phantom results. The authors have taken a different approach and used the analysis of real data directly as a measure with which to compare 3 reconstruction algorithms: 3DRP, iterative filtered backprojection with median root prior (IFBP-MRP), and Fourier rebinning followed by two-dimensional (2-D) filtered backprojection (FORE-FBP) for [ 15O] PET. Two subjects, each with 32 scans acquired in four sessions during a finger opposition motor task, are analyzed using subtraction. A fixed volume-of-interest (VOI) measurement in regions related to the task demonstrates that at high resolution, IFBP-MRP has the best signal-to-noise performance followed by 3DRP and FORE-FBP; however, this advantage gradually diminishes as the resolution decreases. For a voxel measurement derived from the image of each reconstruction, all 3 algorithms are capable of detecting highly activated regions. Although there are some differences in the size, shape, and center location of the activated foci, the authors' preliminary results suggest that IFBP-MRP does offer enhanced signal with some noise control compared with 3DRP- - for the analysis of high-resolution images. If images are to be analyzed at an intermediate to lower resolution, FORE-FBP provides a significant reduction of reconstruction time compared with 3DRP.