Using cell size, cell density, and microscopic growth pattern, 20 duodenal stromal tumors were initially separated into benign and malignant categories. The 10 histologic benign tumors had uniform spindle cells, low cellularity, and an organoid pattern. All had round eosinophilic collagen blobs scattered among the spindle cells, were 4.5 cm or less in maximum diameter, and had two or fewer mitoses per 50 high-power fields (HPF). None metastasized or recurred during a median follow-up of 7 years. In contrast, the 10 histologically malignant tumors were highly cellular, all had two or more mitoses per 50 HPF, and all but one had diameters of 4.5 cm or greater, the exception being 4 cm. Eight cases also had benign-appearing areas, usually submucosal. Eight patients died with disease a median of 31 months after resection, almost all with liver metastases. One patient is alive with metastasis at 13 years. The patient with the 4-cm malignant tumor is disease free at 49 months. All 15 cases were strongly vimentin positive, 11 had S-100 protein, and seven had the CD34 marker. None were desmin or actin positive. No immunophenotype separated benign from malignant. The proliferation marker, proliferating cell nuclear antigen, correlated with histologic diagnosis and clinical outcome, but Ki-67 did not. Based on light microscopic features alone, benign and malignant duodenal stromal tumors can be separated from each other. Tumors with large cells and an organoid pattern are predictably benign; in this study, these tumors measured 4.5 cm or less in diameter and had fewer than 2 mitoses per 50 HPF. Highly cellular tumors with small cells and little or no organoid pattern are malignant. They usually have a diameter greater than 4.5 cm and more than two mitoses per 50 HPF, and they are usually fatal. Immunostaining for cytoplasmic proteins and proliferation markers offers no additional prognostic information to the light microscopic appearances. These conclusions apply only to duodenal tumors; whether they also apply to stromal tumors of the jejunum and ileum is not known.