Patients who receive neoadjuvant chemotherapy for locally advanced breast cancer and have four or more ipsilateral axillary lymph nodes involved at surgery are at high risk for recurrence, with a median time to relapse of 18 months. We offered such patients high-dose chemotherapy with stem cell rescue. Patients received cyclophosphamide or paclitaxel and granulocyte colony-stimulating factor (G-CSF) to mobilize stem cells. Melphalan 140 mg/m2 was then given with stem cell rescue. Twenty-four to 35 days later, thiotepa 900 mg/m2 was given with stem cell rescue. Patients with hormone receptor-positive tumors received tamoxifen. We treated 14 patients in this fashion from 1995 to 1998. The mean age was 46.7 years. The majority of cancers were stage IIIB (79%). Thirteen women underwent mastectomy after anthracycline-containing chemotherapy and 50% had more than seven positive lymph nodes. Hospitalization was principally for neutropenic fever. Other morbidities were pneumonitis, cardiomyopathy, and grade 3/4 white blood cell (WBC) toxicity. No patient died of a treatment-related complication. Seven of 14 relapsed at 10, 12, <15, 15, 17, 21, and 36 months, with median follow-up of 26.5 months. Time to relapse in this small series is only modestly improved over historical experience with standard-dose adjuvant chemotherapy. Alternative strategies for treating locally advanced breast cancer should be pursued.