Purpose: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival [PFS]) and to explore the degree of cross- resistance between the two agents. Patients and Methods: Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m2, 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m2, intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. Results: Objective response in first-line therapy was significantly better (P = .003) for doxorubicin (response rate [RR], 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P < .001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P = .38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. Conclusion: At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting. (C) 2000 American Society of Clinical Oncology.