Background: Sarcomas arising in the gastrointestinal (GI) tract are rare tumors. Molecular markers could be associated with prognosis in these types of tumors. Methods: We performed a retrospective analysis of adult patients with sarcomas arising in the GI tract at the National Institute of Medical Sciences in Mexico City and the University of Alabama at Birmingham Hospital. All histological types were included. Patient, tumor, and treatment factors were analyzed, with overall survival as the main outcome variable. Expression of p53 and cellular proliferation antigen Ki-67 was also analyzed. Statistical analysis was performed by log-rank test and Cox regression. Significance was defined as P < .05. Results: Forty-seven patients were analyzed. The median patient age was 53 years (range, 16-82 years). Twenty-five patients (53%) were women. The stomach was the most common site of presentation. The mean tumor size was 14 cm (2-45 cm). A complete resection was achieved in 40 patients. With a median follow-up of 30 months, the actuarial 3-year survival was 68%. Univariate analysis identified overexpression of p53 and Ki-67, high tumor grade, tumor size >10 cm, and incomplete resection as significant negative prognostic factors. Hispanic race and good performance status were significantly associated with prolonged survival. On multivariate analysis, overexpression of p53 was the only independent negative prognostic factor. Conclusions: Overexpression of p53 is the strongest predictor of poor prognosis in patients with sarcomas of the GI tract. © 2003 The Society of Surgical Oncology, Inc.