BackgroundMisregistration between CT and PET data can result in mis‐localization and inaccurate quantification of functional uptake in whole body PET/CT imaging. This problem is exacerbated when an abnormal inspiration occurs during the free‐breathing helical CT (FB CT) used for attenuation correction of PET data. In data‐driven gated (DDG) PET, the data selected for reconstruction is typically derived from the end‐expiration (EE) phase of the breathing cycle, making this potential issue worse.PurposeThe objective of this study is to develop a deformable image registration (DIR)‐based respiratory motion model to improve the registration and quantification between misregistered FB CT and PET.MethodsTwenty‐two whole‐body 18F‐FDG PET/CT scans encompassing 48 lesions in misregistered regions were analyzed in this study. End‐inspiration (EI) and EE PET data were derived from −10% to 15% and 30% to 80% of the breathing cycle, respectively. DIR was used to estimate a motion model from the EE to EI phase of the PET data. The model was then used to generate PET images at any phase of up to four times the amplitude of motion between EE and EI for correlation with the misregistered FB CT. Once a matched phase of the FB CT was determined, FB CT was deformed to a pseudo CT at the EE phase (DIR CT). DIR CT was compared with the ground truth DDG CT for AC and localization of the DDG PET.ResultsBetween DDG PET/FB CT and DDG PET/DIR CT, a significant increase in ∆%SUV was observed (p < 0.01), with median values elevating from 26.7% to 42.4%. This new method was most effective for lesions ≤3 cm proximal to the diaphragm (p < 0.001) but showed decreasing efficacy as the distance increased. When FB CT was severely misregistered with DDG PET (>3 cm), DDG PET/DIR CT outperformed DDG PET/FB CT alone (p < 0.05). Even when patients showed varied breathing patterns during the PET/CT scan, DDG PET/DIR CT still surpassed the efficiency of DDG PET/FB CT (p < 0.01). Though DDG PET/DIR CT couldn't match the performance of the DDG PET/CT ground truth (42.4% vs. 53.6%, p < 0.01), it reached 84% of its quantification, demonstrating good agreement and a strong overall correlation (regression coefficient of 0.94, p < 0.0001). In some cases, anatomical distortion and blurring, and misregistration error were observed in DIR CT, rendering it still unable to correct inaccurate localization near the boundaries of two organs.ConclusionsBased on the motion model derived from gated PET data, DIR CT can significantly improve the quantification and localization of DDG PET. This approach can achieve a performance level of about 84% of the ground truth established by DDG PET/CT. These results show that self‐gated PET and DIR CT may offer an alternative clinical solution to DDG PET and FB CT for quantification without the need for additional cine‐CT imaging. DIR CT was at times inferior to DDG CT due to some distortion and blurring of anatomy and misregistration error.