Purpose: The aim of this study is to assess a software-based method with semiautomated correction for partial volume effect (PVE) to quantify the metabolic activity of pulmonary malignancies in patients who underwent non-gated and respiratory-gated 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG)-positron emission tomography (PET)/x-ray computed tomography(CT). Procedures: The study included 106 lesions of 55 lung cancer patients who underwent respiratory-gated FDG-PET/CT for radiation therapy treatment planning. Volumetric PET/CT parameters were determined by using 4D PET/CT and non-gated PET/CT images. We used a semiautomated program employing an adaptive contrast-oriented thresholding algorithm for lesion delineation as well as a lesion-based partial volume effect correction algorithm. We compared respiratory-gated parameters with non-gated parameters by using pairwise comparison and interclass correlation coefficient assessment. In a multivariable regression analysis, we also examined factors, which can affect quantification accuracy, including the size of lesion and the location of tumor. Results: This study showed that quantification of volumetric parameters of 4D PET/CT images using an adaptive contrast-oriented thresholding algorithm and 3D lesion-based partial volume correction is feasible. We observed slight increase in FDG uptake by using PET/CT volumetric parameters in comparison of highest respiratory-gated values with non-gated values. After correction for partial volume effect, the mean standardized uptake value (SUVmean) and total lesion glycolysis (TLG) increased substantially (p value G0.001). However, we did not observe a clinically significant difference between partial volume corrected parameters of respiratory-gated and non-gated PET/CT scans. Regression analysis showed that tumor volume was the main predictor of quantification inaccuracy caused by partial volume effect.Electronic supplementary material The online version of this article (doi:10.1007/s11307-014-0776-6) contains supplementary material, which is available to authorized users.Correspondence to: Abass Alavi; e-mail: abass.alavi@uphs.upenn.edu Conclusions: Based on this study, assessment of volumetric PET/CT parameters and partial volume effect correction for accurate quantification of lung malignant lesions by using respiratory non-gated PET images are feasible and it is comparable to gated measurements. Partial volume correction increased both the respiratory-gated and non-gated values significantly and appears to be the dominant source of quantification error of lung lesions.