Altered expression of cell cycle regulatory proteins in GISTs (gastrointestinal stromal tumors) may be the mechanism for their diversity in clinical behavior. The use of these tumorigenetic and cell proliferative proteins may provide an alternative route for follow-up and treatment. The aim of this study was to determine the prognostic relevance of the E2F1 and p16 expression in GISTs. Tissues from 21 cases with GIST were collected retrospectively. Tumor grade was designated according to the consensus system. Immunohistochemistry was done with antibodies against Ki-67, p16, E2F1. For statistical analysis, Ki-67 proliferation index was evaluated in 2 categories: <= 10% and > 10%, whereas p16 expression was scored as negative or positive. E2F1 expression cutoff values were tested for risk group variables as > 5% and > 10%. Correlation between the presence of necrosis, Ki-67 proliferation index, p16, E2F1 expression and the risk grade was determined by Spearman correlation test. Sensitivity and specificity were determined by Fisher exact test with P <= 0.05 considered as significant. High E2F1 expression (over 10%) and high Ki-67 proliferation index (over 10%) correlated significantly with increasing risk grade. There was also a significant correlation between the presence of necrosis and high-risk grade. No correlation was found between the risk grade and p16 expression. Our results suggest that in addition to high Ki-67 proliferation index, high E2F1 expression may also be a useful predictive marker for malignant potential of GISTs.