Doxorubicin (Adriamycin) is an anthracycline effective in breast cancer. Despite a worldwide acceptance of Adriamycin in the adjuvant chemotherapy to maximize the survival benefit in the higher risk patients with breast cancer with promising results, oncologists in general do not favorably consider anthracyclines in the adjuvant treatment setting because of concern about the acute and chronic drug-related toxicity. For high-risk patients with breast cancer with more than three positive axillary lymph nodes, this series adopted a modified sequential regimen of ACMF first with Adriamycin (A) as a single agent in 3-weekly administration for three courses, and then a combination of cyclophosphamide, methotrexate, fluorouracil (CMF) every 3 to 4 weeks for six courses given in an outpatient setting concurrent with radiation therapy as an adjuvant treatment. A total of 56 patients underwent modified radical mastectomy and 3 others breast conservation surgery for their invasive breast cancer. Forty-seven (84%) patients completed the intended adjuvant treatment and 1 patient died of infection from treatment-related neutropenia. As a whole, the 3-year overall survival and disease-free survival rates of 56 patients analyzed were 82.3% and 64.4%, respectively. In this high-risk group, patients with four to nine positive nodes showed a slightly better trend of survival than those with 10 or more positive nodes without reaching statistically significant difference (36-month overall survival: 90.9% vs. 72.5%, p = 0.06; disease-free survival: 78.7% vs. 47.8%, p = 0.38). In this entire group of patients, locoregional recurrence was absent. A total of 55 episodes of grade III and IV hematologic toxicity were observed, with only one death from neutropenic sepsis. This modified ACMF regimen offers a good survival rate in breast cancer patients with more than three positive axillary lymph nodes. When these patients are carefully managed, the morbidity and mortality related to the treatment are low.