Recently, we were able to demonstrate the favourable indication of H-ras expression in the clinically very important group of node-negative breast cancer patients. In order to further resolve a conceivable cellular effect mediated by the H-ras signal transduction pathway, we ascertained the apoptotic activity of the tumor cells of this overall 298 patients group. To this end, fragmented genomic DNA of breast cancer tissue was determined by specific DNA-end-labelling and subsequent visualization, thereby indicating early apoptosis induction. Tissues were considered apoptotic by means of the apoptotic index (quotient of apoptotic tumor cells and total tumor cells). One hundred and eighty-nine tumors (63.4%) were negative for apoptosis and 109 tissues (36.6%) were considered apoptotic (mean apoptotic index 11.9%, range, 0 to 90%). H-ras expression correlated significantly (chi2-test, p=0.004) to apoptosis. Furthermore, restricted to the node-negative subgroup, both H-ras expression and apoptosis were indicative of a better outcome (log-rank test p=0.0001, and p=0.012, respectively) during the observation time (median 87 months). These data suggest that H-ras expression effects the particular breast tumor cells by induction of apoptosis in breast cancer patients in an early stage without node involvement. The study indicates a possible mechanism, by which H-ras may act protectively.