Motion-induced misalignment between transmission and emission scans can result in erroneous estimation of regional tissue activity concentrations. If this motion is of a random nature, mismatch between transmission and emission scans is likely to result in diminished signal-to-noise ratios. In the case of task-related motion, however, corresponding systematic reconstruction artefacts may lead to false-positive or false-negative results. The purpose of the present study was to investigate whether implementation of an image registration (IR) method, which allows for motion-corrected attenuation correction, would improve accuracy of H2 15O PET activation studies. To evaluate the performance of this method, phantom studies as well as studies in human subjects were performed. Results were compared with three alternative methods: standard attenuation correction without motion correction, calculated attenuation correction, and no attenuation correction. The phantom measurements showed that, for quantitative assessment of regional activity concentrations, the IR method was superior to the other attenuation correction methods. In a single-subject study with intentional task-related motion during a visual stimulation paradigm, false-positive results, obtained with the standard attenuation correction method, disappeared after attenuation correction using the IR method. Finally, a group analysis of 11 patients indicated that an increase in signal-to-noise ratio was obtained with the IR method. Therefore, in our view, the IR method should be considered as a first choice for attenuation correction in PET activation studies.