The combined effect of high energy shock waves (HESW), generated by a piezoelectric device, and paclitaxel on Mat B-III rat breast cancer cells in vitro and in an in vivo animal model is presented. A significant reduction of in vitro Mat B-III cell proliferation versus cells treated with paclitaxel alone was observed with the combined exposure to paclitaxel (0.1, 1, or 10 nM) and HESW (0.22 mJ/mm2, 1000 shots). Moreover earlier induction and enhanced apoptosis occurred in cells subjected to the combined treatment with paclitaxel and HESW at 1 and 10 nM versus paclitaxel alone (p<0.01 and p<0.001, respectively). The percentage of apoptotic cells along with BAD mRNA expression, confirm a significant enhancement of apoptosis in tumor tissues subjected to the combined treatment with paclitaxel (2.5 mg/kg on days 7 and 11) and HESW (0.50 mJ/mm2, 500 shots on day 11) in comparison with paclitaxel alone. In conclusion, these data suggest that HESW enhance paclitaxel cytotoxicity in the Mat B-III syngeneic model of breast cancer.