Objective: The purpose of this article is to assess the role of diffusion-weighted MRI in characterizing adrenal masses. Materials and Methods: A retrospective review of the MRI database from August 2007 to July 2009 was performed. The MRI examinations of 48 patients, with 49 lesions, were reviewed independently and blindly by two experienced abdominal radiologists who measured the signal intensities on in-phase and opposed-phase T1-weighted imaging and apparent diffusion coefficient (ADC). ADC measurements and quantitative parameters of chemical shift imaging (signal intensity index and adrenal-to-spleen ratio) were assessed separately and in combination. Lesions with indeterminate signal intensity index (< 16.5%) were considered benign if ADC was greater than or equal to 1.0 × 10(-3) mm(2)/s and malignant if ADC was less than 1.0 × 10(-3) mm(2)/s. Stepwise logistic regression analysis and receiver operating characteristic curves analysis were performed. Results: There were 12 malignant and 37 benign lesions. On multivariate analysis, the only significant predictors of lesion status were signal intensity index from reviewer 2 (p = 0.05) and lesion size (p = 0.04); ADC values were not found to be useful. On receiver operating characteristic curve analysis, there was no significant difference in area under the curve for ADC, signal intensity index, adrenal-to-spleen ratio, or the combined signal intensity index and ADC assessment. For lesions that were indeterminate according to signal intensity index, ADC values greater than 1.50 × 10(-3) mm(2)/s were found only in benign lesions, and nine of 11 lesions with ADC less than 1.0 × 10(-3) mm(2)/s were malignant. Conclusion: In general, ADC values are not useful in differentiating adrenal lesions. However, when ADC values are applied to lesions that are indeterminate on signal intensity index, they may help in differentiating a subset of benign and malignant lesions.