CT-guided fine-needle aspiration (FNA) of lung lesions is subject to sampling errors. The current study assessed whether information provided by (18)F-FDG PET/CT will decrease the false-negative (FN) rate and thus improve the accuracy of CT-guided FNA. Data from 311 consecutive patients with lung nodules who underwent (18)F-FDG PET/CT and CT-guided FNA within an interval of less than 30 d were retrospectively assessed. In-house-developed software was used to register CT images performed for the FNA procedure (CT FNA) with corresponding slices of the PET/CT study. The quality of registration was rated on a scale of 1 (excellent) to 5 (misregistration). Only cases scored 1 or 2 were further evaluated. The software provided the highest standardized uptake value (SUV) within the lesion and at the location of the tip of the aspirating needle. The distance between the tip and the area with the highest SUV within the lesion was measured. The mean distance from the tip of the needle to the focus with the highest SUV, as well as the mean difference between the maximum SUV in the whole lesion and at the needle tip, was calculated and compared for cases with true-positive (TP) and FN FNA results. Anatomic and metabolic parameters of lesions included in these 2 groups were also compared. There were 267 patients (86%) with score 1 or 2 registration quality for CT FNA and PET/CT/CT images, including 179 TP (67%), 5 false-positive (FP, 2%), 49 true-negative (TN, 18%), and 34 FN (13%) FNA results. The distance between the location of the needle tip and the focus with the highest SUV in the lesion was significantly greater in the FN group (15.4 ± 14 mm) than in the TP group (5.9 ± 13.4 mm, P < 0.001). The maximum SUV at the location of the aspirating needle tip was significantly higher in the TP group, at 6.4 ± 6.4, than in the FN group, at 4 ± 4.7 (P < 0.05). The present results demonstrate a relationship between the degree of metabolism at the site of tissue-sampling aspiration in lung lesions and the accuracy of FNA results. Anatomy- and metabolism-based FNA guidance using information provided by both (18)F-FDG PET and CT may improve the accuracy of histologic examinations, decrease the rate of FN results, and thus increase the probability of achieving a definitive diagnosis.