Zoledronic acid (ZA) is the most widely used bisphos-phonate to treat cancer-induced bone disease. There is evidence that bisphosphonates have direct antitumor activity and that their combination with anticancer agents can significantly enhance the effect of treatment. We evaluated whether the combination of ZA with different platinum compounds exerts a synergistic effect in breast cancer cell lines and we investigated the mechanisms of action involved. This study was performed on four breast cancer cell lines, MCF-7, SKBR3, MDA-MB-231 and BRC-230, and confirmed on a primary culture obtained from a breast cancer bone metastasis specimen. ZA (50 µM) was administered for 72 h alone or in combination with cisplatin (Cis) or carboplatin. Drug-induced growth inhibition was detected by sulforhodamine B assay, apoptosis and cell cycle regulation were detected by flow cytometry, and protein expression was evaluated by western blot analysis. MCF-7 and SKBR3 showed very low sensitivity to the three drugs tested. The ZA + Cis combination exerted a high antitumor activity in the two triple-negative lines MDA-MB-231 and BRC-230. An important synergistic effect was obtained in MDA-MB-231 and an additive effect was observed in BRC-230. The p21, pMAPK and m-TOR pathways were regulated by this combined treatment, particularly at lower Cis doses. Carboplatin did not show antitumor activity either alone or in combination with ZA. In conclusion, the potential novel treatment schedule identified for triple-negative breast cancer could prove beneficial in view of the limited therapeutic options available for patients and also since the synergism with ZA would enable lower Cis doses to be used, thus reducing toxicity. Although further research in a clinical setting is warranted, our results on cell lines has been confirmed on a human primary bone metastasis culture.