Background: Adrenal-protocol CT is commonly performed to distinguish adrenal adenomas from other adrenal tumors. However, the technique's utility among heterogeneous nodules is not well established, and the optimal method for placing ROIs in heterogeneous nodules is not clearly defined. Objective: To determine the diagnostic performance of adrenal-protocol CT to distinguish adenomas from non-adenomas among heterogeneous adrenal nodules, and to compare this performance among different methods for ROI placement. Methods: This retrospective study including 164 patients (mean age, 59.1 years; 61 men, 103 women) from seven institutions, with a total of 164 heterogeneous adrenal nodules evaluated by adrenal-protocol CT. All nodules had an available pathologic reference standard. A single investigator at each institution evaluated CT images. ROIs were placed on portal venous phase images using four ROI methods: standard ROI, single large ROI in nodule center; high ROI, single ROI on nodule's highest-attenuation area; low ROI, single ROI on nodule's lowest-attenuation; average ROI: mean of three ROIs on nodule's superior, middle, and inferior thirds using the approach for the standard ROI. ROIs were then placed in identical locations on unenhanced and delayed phases. Absolute washout was determined for all methods. Results: The nodules comprised 82 adenomas and 82 non-adenomas (36 pheochromocytomas, 20 metastases, 12 adrenocortical carcinomas, and 14 with other pathologies). Mean nodule size was 4.5±2.8 cm (range, 1.6-23.0 cm). Unenhanced CT attenuation of 10 HU or less exhibited sensitivity and specificity for adenoma of 22.0% and 96.3% for standard ROI, 11.0% and 98.8% for high ROI, 58.5% and 84.1% for low ROI, and 30.5% and 97.6% for average ROI methods. Adrenal-protocol CT overall (unenhanced attenuation of 10 HU or less, or absolute washout of 60% or greater) exhibited sensitivity and specificity for adenoma of 57.3% and 84.1% for standard ROI, 63.4% and 51.2% for high ROI, 68.3% and 62.2% for low ROI, and 59.8% and 85.4% for average ROI methods. Conclusion: Adrenal-protocol CT has poor diagnostic performance for distinguishing adenomas from non-adenomas among heterogeneous adrenal nodules, regardless of the method used for ROI placement. Clinical Impact: Adrenal-protocol CT has limited utility in the evaluation of heterogeneous adrenal nodules.