Gastrointestinal stromal tumors (GISTs) are c-Kit-positive neoplasms of the digestive tract. Few studies have reported their real incidence and malignancy. Two systems of risk assessment of aggressive behavior were recently proposed. The aims of our study were (1) to ascertain the frequency of GISTs and their clinical behavior in a large series of cases with a long-term follow-up, (2) to evaluate the prognostic value of two well-known risk assessment classifications, and (3) to propose an alternative prognostic index based on our data. Statistical analyses were performed to identify possible predictors of malignant behavior. One hundred and eighteen out of 169 (70%) mesenchymal tumors were GISTs. They were located in the stomach (57%), small intestine (31%), colon/rectum (6%), and omentum/mesentery (6%). Eighteen cases (16%) showed malignant behavior, with local recurrence in eight cases and distant metastases in 11 cases. Fifteen of 114 (13%) patients died of disease within 74 months, whereas 63 (55%) patients were still alive after a median period of 78 months. At multivariate analysis, high-risk category (according to Fletcher's criteria), omental/colorectal site, and younger patient age were independent predictors of malignant behavior. In addition to the evaluation of risk category, tumor site and patient age helped to better identify patients requiring stricter monitoring.