Purpose: To develop an algorithm to maximize the diagnostic yield of positron emission tomography (PET)/computed tomography (CT) by using defined attenuation and standardized uptake value (SUV) criteria. Materials and Methods: An IRB-approved, HIPAA-compliant retrospective review with waiver of informed consent of data in 1388 consecutive patients who underwent PET/CT for known or suspected lung cancer was completed, and 187 adrenal nodules were identified in 147 patients. Nodules were defined histologically or by size change (malignant, n = 37) or stability for more than 1 year (benign, n = 58). Nodules not sampled for biopsy and with less than 1 year of follow-up were considered indeterminate (n = 92). Diameter, mean attenuation, SUV max, and SUV ratio (nodule SUV max/liver SUV avg) were compared with t test and receiver operating characteristic analyses. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for diameter > 3 cm, mean attenuation > 10 HU, nodule SUV max > 3.1, and SUV ratio > 1.0. These were also calculated for higher SUV max and SUV ratio thresholds that were found to exclude all false-positives. Diagnostic accuracy was compared by using the McNemar test (P < .05). Results: In the study group of 147 patients (aged 42-88 years; mean, 65.5 years; 59 women), combined PET/CT with mean attenuation > 10 HU and SUV max > 3.1 had 97.3% sensitivity and 86.2% specificity. Combined PET/CT with mean attenuation > 10 HU and SUV ratio > 1.0 had 97.3% sensitivity and 74.1% specificity. The accuracies of these threshold combinations (90.5% and 83.2%, respectively) were significantly different (P = .008). Applying a further cutoff of SUV ratio > 2.5 enabled identification of 22 of 37 metastatic lesions and exclusion of all fluorodeoxyglucose- avid benign nodules. Conclusion: Definitive identification of many metastases can be accomplished by applying an SUV ratio cutoff of greater than 2.5, allowing pragmatic management of adrenal nodules that initially test positive with the combined PET/CT criteria SUV max > 3.1 and mean attenuation > 10 HU. © RSNA, 2009.