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The potential for malignancy of an islet cell tumor of the pancreas is difficult to cytologically judge when one evaluates only the primary lesion, because a malignant condition is usually determined by the presence of regional or distant metastases. Nuclear DNA cytometric measurements have proved helpful both in the evaluation of the malignant potential of other endocrine and nonendocrine lesions and in the determination of the "aggressiveness" of these tumors. Thirty-six islet cell tumors or their metastases from 25 patients were studied. Eleven patients had insulinomas and typical insulinoma syndromes, and 14 others had gastrinomas with the Zollinger-Ellison syndrome. Tissue from each tumor was stained by the Feulgen technique, and nuclear DNA cytometry was performed by means of the microTICAS system designed by the Cytopathology Laboratory of the University of Chicago. Ploidy measurements of insulinomas, taken alone, did not discriminate well between benign and malignant states. However, the single malignant insulinoma could be clearly recognized, for it was one of only two lesions in that group with 5N-exceeding rate (5N-ER) values of 1% or greater. (5N-ER is defined as the percentage of aneuploid nuclei with nuclear DNA content greater than 5N.) On the other hand, seven of eight malignant gastrinomas had ploidy values of 2.5N or greater (our definition of an aneuploid state) and/or had 5N-ER values of 1% or greater, while five of six benign gastrinomas had ploidy values of less than 2.5N and had 5N-ER values of 0%. In addition, the two most aggressive tumors had the highest ploidy and 5N-ER values. Nuclear DNA cytometric studies appear to offer promise as an aid in the evaluation of pancreatic islet cell tumors, particularly gastrinomas.