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Background We explored the role of dual time point fluorodeoxyglucose positron emission tomography/computed tomography (DTP PET/CT) scan in the differentiation of benign and malignant lung and mediastinal lesions. Methods We studied a sample of 72 consecutive patients who underwent DTP PET/CT scan for intrathoracic lesions. Information on demographics, initial and delayed maximum standardized uptake values (SUVmax) of lesions and final diagnosis were collected. Clinical criteria to diagnose benign lesions were defined as stability or regression of the lesion on follow-up after 2 years of initial detection. Sensitivity, specificity, predictive values and likelihood ratio and retention index were calculated using standard methods. Results Sixty-three (87%) patients had increased SUVmax in delayed scan (1 hour after initial scan). Among the patients with increased delayed uptake, 51 (80%) had malignant lesion and 12 (20%) had nonmalignant lesions. All 9 patients whose SUVmax decreased on delayed scan had nonmalignant lesions. The increased SUV on delayed scan was 100% sensitive in diagnosis of cancer but was only 42% specific. The positive predictive value was 80%, whereas the negative predictive value was 100%. Likelihood ratio for positive test was 1.75. Conclusions All the lesions with decreased SUVmax in delayed PET scan were nonmalignant. This was true for both lung and mediastinal lesions. This could be a very helpful diagnostic finding in areas with high prevalence of benign conditions such as histoplasmosis and sarcoidosis. Multiple invasive diagnostic modalities could be prevented in a significant percentage of patients, with attendant decrease in morbidity and health care costs.