S-1 was found to be highly effective against metastatic hepatic lesions from multiple drug-resistant breast cancers, in 2 patients. The details of these cases are presented below. Case 1, a 59-year-old woman, was HER2-positive. For chemotherapy following a recurrence, trastuzumab+weekly paclitaxel and trastuzumab+vinorelbine regimens were attempted, but the hepatic metastasis worsened. On the other hand, a trastuzumab+S-1 regimen resulted in a notable reduction in the metastatic foci of the liver approximately one month after the initiation of the therapy. This effect was sustained for 5 months thereafter. Case 2 involved a 67-year-old woman with HER2-negative breast cancer. Following a recurrence, chemotherapeutic agents, such as taxane and vinorelbine, were applied, which all resulted in PD. Treatment with S-1 alone reduced the size of the hepatic metastatic lesion, as seen in case 1. Currently (14 months after the initial treatment with S-1), therapeutic efficacy has been maintained. Adverse effects were minimal and QOL was not compromised in either case. We speculate that S-1 is not only effective as a therapeutic agent but is also useful in view of safety and QOL.