Topical treatment of skin metastases with a cytotoxic agent is attractive for its easy self-administration and absence of major systemic interference. Miltefosine exerts its cytotoxicity by acting on cell membrane phospholipids and can be administered topically. Twenty breast cancer patients with progression of skin metastases were treated with a 6% solution of miltefosine, which was topically administered once daily during the first week and twice daily thereafter. Sixteen out of 20 patients also had metastatic disease at other sites. Concomitant systemic treatment when ongoing for at least 2 months prior to study entry was permitted, and consisted of chemotherapy and hormonal therapy in seven and nine patients, respectively. Prior palliative cytotoxic and hormonal therapy had been administered to 11 and 19 patients, respectively. No grade 3 and 4 toxicity occurred. Miltefosine therapy was discontinued in two patients due to nausea and in one patient due to skin toxicity. Grade 1 and 2 adverse skin reactions, and nausea and vomiting were seen in 11 and two patients, respectively. In 18 patients evaluable for response, four partial responses were noted (response rate 22%), while seven patients had stable disease. Three partial responses were observed in patients in whom the skin lesions were smaller than 1.5 cm2. Median duration of response was 2.5 months and median time to progression for all patients was 1.9 months. In this study topically applied miltefosine for metastatic skin lesions of breast cancer showed modest activity in a relatively heavily pretreated patient population, without serious systemic toxicity.