We have investigated the immunohistochemical expression of thymidine phosphorylase before and after the administration of anthracycline, and/or anthracycline/taxane-based preoperative chemotherapy in a consecutive series of 55 patients with primary operable breast cancer. Pretreatment, large core breast biopsies and the corresponding surgical samples were retrospectively evaluated for thymidine phosphorylase immunoreactivity. Immunohistochemical expression was evaluated on tumor cells (nuclear and cytoplasmic staining) and on stromal cells (cytoplasmic staining). The cytoplasmic expression of thymidine phosphorylase was enhanced in the tumor cells after treatment (P=0.04). An increase in thymidine phosphorylase cytoplasmic tumor expression was observed in 33% (95% confidence interval: 19-50%) of patients after preoperative chemotherapy (P=0.01). No statistically significant nuclear staining changes were observed in response to treatment. Similarly, no significant changes of the enzyme expression were seen in stromal cells. This study provides further evidence that, at least in breast cancer, thymidine phosphorylase is upregulated after anthracycline and/or taxane-containing chemotherapy. Accordingly, it supports the hypothesis of a synergistic effect between thymidine phosphorylase-modulating and thymidine phosphorylase-targeting anticancer agents. Translational studies, specifically designed on the basis of this rationale, are eagerly waited.