Objective This study was performed to evaluate the effects of intravenous (i.v.) contrast agent on semi-quantitative values and lymph node (LN) staging of F-18-fluorodeoxyglucose positron emission tomography/computed tomography (F-18-FDG PET/CT) in patients with lung cancer. Methods Thirty-five patients with lung cancer were prospectively included. Whole-body PET and nonenhanced CT images were acquired 60min following the i.v. injection of 370MBq F-18-FDG and subsequently, enhanced-CT images were acquired with the i.v. administration of 400mg iodinated contrast agent without positional change. PET images were reconstructed with both nonenhanced and enhanced CTs, and the maximum and average standardized uptake values (SUVmax and SUVave) calculated from lung masses, LNs, metastatic lesions, and normal structures were compared. To evaluate the effects of the i.v. contrast agent on LN staging, we compared the LN status on the basis of SUVs (cut-offs; SUVmax = 3.5, SUVave = 3.0). Results The mean differences of SUVmax in normal structures between enhanced and nonenhanced PET/CT were 15.23% +/- 13.19% for contralateral lung, 8.53% +/- 6.11% for aorta, 5.85% +/- 4.99% for liver, 5.47% +/- 6.81% for muscle, and 2.81% +/- 3.05% for bone marrow, and those of SUVave were 10.17% +/- 9.00%, 10.51% +/- 7.89%, 4.95% +/- 3.89%, 5.66% +/- 9.12%, and 2.49% +/- 2.50%, respectively. The mean differences of SUVmax between enhanced and nonenhanced PET/CT were 5.89% +/- 3.92% for lung lesions (n = 41), 6.27% +/- 3.79% for LNs (n = 76), and 3.55% +/- 3.38% for metastatic lesions (n = 35), and those of SUVave were 3.22% +/- 3.01%, 2.86% +/- 1.71%, and 2.33% +/- 3.95%, respectively. Although one LN status changed from benign to malignant because of contrast-related artifact, there was no up- or down-staging in any of the patients after contrast enhancement. Conclusions An i.v. contrast agent may be used in PET/CT without producing any clinically significant artifact.