Breast cancer patients who are positive for estrogen receptor (ER) are usually treated with anti-estrogen drugs, such as tamoxifen (Tam). However, a great majority of such patients eventually develop resistance to Tam. In this study, MCF-7 cells (with de novo and/or acquired resistance to Tam) as well as T47D cells (acquired resistance to Tam) models were used to investigate the effect of treatment with cisplatin plus tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The results in the two cell types treated with cisplatin plus TRAIL showed significantly increased cell death compared to that in the untreated control cells. A similar treatment had a minimal effect on normal breast cells, the increased cell death appeared to be caused by the activation of caspases and, inhibition of the activity of caspases (using relatively specific inhibitors) reduced the cell death caused by cisplatin plus TRAIL treatment. Taken together, the results suggested that cisplatin plus TRAIL treatment has the potential to provide a novel treatment strategy to improve the treatment outcome in anti-estrogen‑resistant breast cancer patients.