Simultaneous flow cytometric quantitation of DNA content and the proliferation-associated nuclear antigen p105 was performed on 41 gastrointestinal smooth muscle neoplasms and the results were correlated with histologic features. Aneuploid DNA stemlines were found in 17 cases (41%), including four of 15 (21%) tumors of unknown malignant potential, eight of 17 (47%) low-grade leiomyosarcomas, and five of seven (71%) high-grade leiomyosarcomas. In 10 of the 17 aneuploid tumors, an aneuploid peak was clearly identified on the single parameter DNA histogram, with a mean DNA index of 1.36. In the other seven aneuploid cases, a near-diploid, aneuploid population (mean DNA index, 1.08) was identified only by simultaneous immunofluorescence for p105. Clinical follow-up information was available for 14 patients. Mean survival of 10 patients with aneuploid tumors was 32 months, whereas mean survival of four patients with diploid tumors was 51 months. Of the seven patients who died within 1 year of diagnosis, six had aneuploid leiomyosarcomas. These findings demonstrate that DNA aneuploidy is common in high-grade gastrointestinal leiomyosarcomas and may be associated with shortened survival.