Purpose To study the feasibility and impact of respiratory gating in positron emission tomographic (PET) imaging in a clinical trial comparing conventional hardware-based gating with a data-driven approach and to describe the distribution of determined parameters. Materials and Methods This prospective study was approved by the ethics committee of the University Hospital of Münster (AZ 2014-217-f-N). Seventy-four patients suspected of having abdominal or thoracic fluorine 18 fluorodeoxyglucose (FDG)-positive lesions underwent clinical whole-body FDG PET/computed tomographic (CT) examinations. Respiratory gating was performed by using a pressure-sensitive belt system (belt gating [BG]) and an automatic data-driven approach (data-driven gating [DDG]). PET images were analyzed for lesion uptake, metabolic volumes, respiratory shifts of lesions, and diagnostic image quality. Results Forty-eight patients had at least one lesion in the field of view, resulting in a total of 164 lesions analyzed (range of number of lesions per patient, one to 13). Both gating methods revealed respiratory shifts of lesions (4.4 mm ± 3.1 for BG vs 4.8 mm ± 3.6 for DDG, P = .76). Increase in uptake of the lesions compared with nongated values did not differ significantly between both methods (maximum standardized uptake value [SUVmax], +7% ± 13 for BG vs +8% ± 16 for DDG, P = .76). Similarly, gating significantly decreased metabolic lesion volumes with both methods (-6% ± 26 for BG vs -7% ± 21 for DDG, P = .44) compared with nongated reconstructions. Blinded reading revealed significant improvements in diagnostic image quality when using gating, without significant differences between the methods (DDG was judged to be inferior to BG in 22 cases, equal in 12 cases, and superior in 15 cases; P = .32). Conclusion Respiratory gating increases diagnostic image quality and uptake values and decreases metabolic volumes compared with nongated acquisitions. Data-driven approaches are clinically applicable alternatives to belt-based methods and might help establishing routine respiratory gating in clinical PET/CT. (©) RSNA, 2016 Online supplemental material is available for this article.