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The diagnosis of cancer by FDG PET-CT is often inaccurate owing to subjectivity of interpretation. We compared the accuracy of a novel normalized (standardized) method of interpretation with conventional non-normalized SUV. Patients (<i>n</i> = 393) with various malignancies were studied with FDG PET/CT to determine the presence or absence of cancer. Target lesions were assessed by two methods: (1) conventional SUV_max (conSUV_max) and (2) a novel method that combined multiple factors to optimize SUV (optSUVmax), including the patient’s normal liver SUV_max, a liver constant (k) derived from a review of the literature, and use of site-specific thresholds for malignancy. The two methods were compared to pathology findings in 154 patients being evaluated for mediastinal and/or hilar lymph node (MHLNs) metastases, 143 evaluated for extra-thoracic lymph node (ETLNs) metastases, and 96 evaluated for liver metastases. OptSUV_max was superior to conSUV_max for all patient groups. For MHLNs, sensitivity was 83.8% vs. 80.7% and specificity 88.7% vs. 9.6%, respectively; for ETLNs, sensitivity was 92.1% vs. 77.8% and specificity 80.1% vs. 27.6%, respectively; and for lesions in the liver parenchyma, sensitivity was 96.1% vs. 82.3% and specificity 88.8% vs. 23.0%, respectively. Optimized SUV_max increased diagnostic accuracy of FDG PET-CT for cancer when compared with conventional SUV_max interpretation.