Reliable indicators of behavior in stromal tumors of the gastrointestinal tract have yet to be elucidated. Aggressive behavior has been associated with large size, hypercellularity, tumor necrosis, nuclear atypia, and high mitotic rate. Recently, new methods of measuring proliferation have been developed that exploit the phenomenon of cell cycle specific protein synthesis. In this study the expression of the S-phase specific nuclear protein proliferating cell nuclear antigen (PCNA) is tested as an indicator of malignancy. Sixteen stromal tumors of the stomach were reviewed for tumor size, cellularity, nuclear atypia, mitotic rate, necrosis, vascular invasion, and predominant cell type. Local recurrence and/or mortality were ascertained with a minimum follow-up of 5 yr. An immunohistochemical assay for PCNA was performed on a paraffin section of tumor and the percentage of positively stained cells ("PCNA index") was determined. Among the nine men and seven women, age 37 to 80 (median 66) yr, two had local recurrences that were treated surgically with no metastases. Only positive resection margin correlated with local recurrence. Two other patients developed distant metastases at 8 and 15 mo and died. Mortality did not correlate with age, sex, size, cellularity, necrosis, cell type, and vascular invasion. High grade nuclear atypia (2/2 versus 1/14, P = 0.02) and high mitotic rate (20.5 versus 5.5 per 40 hpfs, P = 0.01) did correlate with mortality. PCNA index did not correlate with local recurrence, but was sharply higher in fatal cases (6.4 versus 1.2, P = 0.001). Both fatal tumors had PCNA values above 6.0, and all others had values of 4.0 or less. The PCNA index is a proliferative marker that may have prognostic value in gastric stromal tumors.