Single-agent docetaxel (Taxotere) treatment has recently demonstrated promising clinical activity in patients with advanced hormone-refractory prostate cancer. Taxanes were recently found to upregulate the tumoral activity of thymidine phosphorylase (TP), a key cellular enzyme [transformation of 5'-deoxy-5-fluorouridine (5'-DFUR) into 5-fluorouracil] in the activation cascade of capecitabine (Xeloda). We tested (cytotoxic effects and molecular mechanisms) the Taxotere-5'-DFUR combination on hormone-refractory prostate cancer cell lines (DU145 and PC3). Cells were exposed to Taxotere and/or 5'-DFUR in three different sequences: Taxotere was given alone for 48 h, then 5'-DFUR was added for 48 h; Taxotere and 5'-DFUR together during 96 h or 5'-DFUR was given alone for 48 h then Taxotere was added for 48 h. The drug sequence Taxotere applied first followed by 5'-DFUR led to synergistic cytotoxic effects on both cell lines; the other sequences resulted in simple additivity. Taxotere did not modify TP activity while it decreased thymidylate synthase activity. There was an increase in CD95 cellular membrane levels following exposure to Taxotere-5'-DFUR, which is in agreement with the supra-additive cytotoxic combination. This observation may serve as a preclinical rationale for a next step testing the Taxotere-capecitabine combination at the clinical level in prostate cancer patients.