Gastrointestinal stromal tumors are a heterogeneous group of neoplasms that have clinical and histologic features that vary depending on their location within the gastrointestinal tract. Prediction of clinical behavior in this group of tumors is notoriously difficult, and the same criteria for malignancy do not necessarily apply to stromal tumors from different sites within the gastrointestinal tract. Using known clinical behavior with long-term follow-up, we attempted to determine which features, if any, are associated with clinical behavior in stromal tumors arising in the stomach, the most common site for such tumors. Seventy-seven gastric stromal tumors were studied and classified as "adverse outcome (AO) tumors" (malignant) or "nonadverse outcome tumors" (benign) based on their known clinical outcome. AO was defined as metastasis and/or death due to tumor. Patients with a non-AO had at least 5 years of tumor/metastasis-free follow-up. Thirty-seven patients had an AO (follow-up [metastasis at presentation] 0-73 months; median 6 months), and 40 patients had a non-AO (follow-up 60-264 months; median 84 months). All cases were reviewed by two authors (J.R.G., H.D.A.), who were blinded to clinical outcome and gross features, and classified as histologically benign or not benign using preset, defined histologic criteria based upon the authors' prior experience with a large number of these tumors. If the tumor did not fit with either the characteristic cellular spindle cell or benign epithelioid cell patterns, the tumor was classified as not benign. Clinical outcome was then correlated with the histologic designation to determine if these preset criteria were valid. The authors were able to accurately classify the tumors as benign or not benign with a sensitivity of 100% and a specificity of 92%. In addition, for all cases individual morphologic and clinical features were examined. Features associated with an AO included tumor size >/=7 cm, high cellularity, mucosal invasion, high nuclear grade, mitotic counts >/=5/50 high power fields, mixed cell type, and the presence of a myxoid background and/or absence of stromal hyalinization. By recognizing several well-defined patterns of benign gastric stromal tumors and the myriad of individual features shown to correlate with an AO, one can better predict the clinical behavior of gastric stromal tumors.