Independently, endocrinology, radiology, and nuclear medicine can not optimally differentiate the etiology of the incidental adrenal mass. Rather, the insight necessary for this task must be contributed by all three disciplines. Incidentally discovered adrenal masses are being detected at an increasing rate. This trend is expected to continue based on the incidence of adrenal masses in autopsy series and the increasing use of high resolution abdominal imaging techniques. CT and MRI are able to definitely characterize only a minority of these lesions (simple cyst, myelolipoma, obvious local malignant invasion). Biochemical screening for hormone excess is essential regardless of a nonsuggestive complete history and physical examination. An argument may be made for not further pursuing nonhypersecreting lesions with the typical features of a benign adenoma on CT scan and an attenuation value of 0 HU or less. Adrenocortical scintigraphy is recommended in all patients with normal biochemical screening tests, especially those with CT attenuation values greater than 0 HU. In this setting, we believe that the functional and anatomical information provided by NP-59 and [75Se]selenomethylnorcholesterol scintigraphy allows one to noninvasively, accurately, and less expensively (Table 9) categorize adrenal masses as benign nonhypersecretory adenomas (the vast majority) vs. a possibly malignant lesion (the minority). In the presence of normal biochemistry, a concordant NP-59 imaging pattern is diagnostic of a nonhypersecretory benign adrenal adenoma and requires no immediate therapeutic intervention. Conversely, patients with discordant patterns of NP-59 scintigraphy have lesions that carry a significant risk for malignancy, and the pursuit of a tissue diagnosis is indicated, usually by means of FNA. Normal adrenocortical tissue on cytological studies in this setting may represent inadvertent sampling of adjacent normal adrenocortical tissues or the presence of a well differentiated adrenocortical carcinoma. In patients with lesions larger than 2 cm in whom NP-59 scintigraphy is nonlateralizing, the possibility of a periadrenal or pseudoadrenal mass is likely and should prompt review, or perhaps even repeat, of high resolution adrenal imaging (occasionally angiography may be helpful). In lesions shown to be 2 cm or less in size with a nonlateralizing NP-59-scan, there is a possibility of a periadrenal or pseudoadrenal mass; however, once this is excluded it must be recognized that benign and malignant lesions, because of the limitations of scintigraphy, cannot always be clearly distinguished by this method when masses are small.(ABSTRACT TRUNCATED AT 400 WORDS)