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Clinicians rely heavily on fluorodeoxyglucose F18–labeled positron emission tomography (FDG-PET) imaging to evaluate lung nodules suspicious for cancer. We evaluated the performance of FDG-PET for the diagnosis of malignancy in differing populations with varying cancer prevalence.To determine the performance of FDG-PET/computed tomography (CT) in diagnosing lung malignancy across different populations with varying cancer prevalence.Multicenter retrospective cohort study at 6 academic medical centers and 1 Veterans Affairs facility that comprised a total of 1188 patients with known or suspected lung cancer from 7 different cohorts from 2005 to 2015.18F fluorodeoxyglucose PET/CT imaging.Final diagnosis of cancer or benign disease was determined by pathological tissue diagnosis or at least 18 months of stable radiographic follow-up.Most patients were male smokers older than 60 years. Overall cancer prevalence was 81% (range by cohort, 50%-95%). The median nodule size was 22 mm (interquartile range, 15-33 mm). Positron emission tomography/CT sensitivity and specificity were 90.1% (95% CI, 88.1%-91.9%) and 39.8% (95% CI, 33.4%-46.5%), respectively. False-positive PET scans occurred in 136 of 1188 patients. Positive predictive value and negative predictive value were 86.4% (95% CI, 84.2%-88.5%) and 48.7% (95% CI, 41.3%-56.1%), respectively. On logistic regression, larger nodule size and higher population cancer prevalence were both significantly associated with PET accuracy (odds ratio, 1.027; 95% CI, 1.015-1.040 and odds ratio, 1.030; 95% CI, 1.021-1.040, respectively). As the Mayo Clinic model–predicted probability of cancer increased, the sensitivity and positive predictive value of PET/CT imaging increased, whereas the specificity and negative predictive value dropped.High false-positive rates were observed across a range of cancer prevalence. Normal PET/CT scans were not found to be reliable indicators of the absence of disease in patients with a high probability of lung cancer. In this population, aggressive tissue acquisition should be prioritized using a comprehensive lung nodule program that emphasizes advanced tissue acquisition techniques such as CT-guided fine-needle aspiration, navigational bronchoscopy, and endobronchial ultrasonography.