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Discrimination between adrenocortical carcinoma and lipid-poor cortical adenoma preoperatively is frequently difficult as these two entities have overlapping imaging characteristics. Differentiation will allow for the selection of the most appropriate operative approach and may help prevent over-treatment. We aimed to identify imaging features that could preoperatively differentiate adrenocortical carcinoma from lipid-poor cortical adenoma and use them in a novel imaging-based score.We conducted a retrospective analysis of patients with pathologically proven adrenocortical carcinoma and lipid-poor cortical adenoma who underwent resection in a single tertiary referral center between March 1998 and August 2020. The inclusion criteria were diameter1 cm, attenuation10 Hounsfield units on nonenhanced computed tomography, and histopathologic diagnosis. Patients with metastatic or locally advanced adrenocortical carcinoma adenoma (stages 3-4) were excluded. We developed a score using binary logistic multivariate regression model in 5-fold derivation (∼70%) cohorts with stepwise backward conditional regression as feature selection. Standardized mean regression weight was used as variable score points.We identified 232 adrenals resected across 211 patients. By comparing the imaging characteristics of adrenocortical carcinoma (n = 56) and lipid-poor cortical adenoma (n = 156), we revealed statistically significant differences between the groups in 9 parameters: size, attenuation, thin and thick rim enhancement patterns, heterogeneity, calcification, necrosis, fat infiltration, and lymph node prominence. The score mean performance was 100% sensitivity for the exclusion of adrenocortical carcinoma, 80% specificity (95% confidence interval, 68.3-91.5), 66% positive predictive value (95% confidence interval, 52.3-78.7), and 100% negative predictive value with area under the curve of 0.974.We defined and evaluated a novel 9-variable, imaging-based score. This score outperformed any single variable and could facilitate safe preoperative discrimination of adrenocortical carcinoma and lipid-poor cortical adenoma.