The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of lonidamine, given in an escalating oral daily schedule to a maximum dose of 450 mg/m2 in patients with previously treated advanced breast cancer. Five responses were seen in 30 evaluable patients (17%). Treatment was discontinued because of toxicity in seven patients. Toxicity generally consisted of myalgia, nausea, vomiting, skin hyperesthesia, somnolence, and ototoxicity. All side effects were reversible and no hematologic toxicity was observed. The absence of myelosuppression and the suggestive lack of cross-resistance between lonidamine and standard chemotherapeutic drugs warrant further studies of lonidamine in breast cancer, particularly in combination with other agents.