Hydroxyurea is an antineoplastic drug with a broad spectrum of clinical activity and minimal nonhematopoietic toxicity. It potentiates the cytotoxicity of alkylating agents and topoisomerase II active drugs in vitro and in vivo. It is not susceptible to alkylating agent-specific or multidrug-type resistance. We have therefore added high-dose oral hydroxyurea to widely used autologous bone marrow transplantation combination chemotherapy regimens for large cell lymphoma and metastatic breast cancer. Seventeen patients with primary-refractory or refractory-relapse large cell lymphoma received oral hydroxyurea (1.5 g/m2 every 6 hours for 12 doses) added to carmustine/cyclophosphamide/etoposide (BCV). Twelve patients with metastatic breast cancer received the same dose oral hydroxyurea added to cyclophosphamide and thiotepa. Mucositis severe enough to require parenteral narcotics was seen in over half of the patients, but none required intubation for airway maintenance. A thrombotic thrombocytopenic purpura-like hemorrhagic syndrome occurred in six patients and was fatal for three. With the BCV/hydroxyurea regimen, this syndrome was seen with the same frequency as with BCV alone. Death from rapidly progressive disease or toxicity occurred in seven of 29 patients (24%). For patients with 6 months' minimum follow-up, four of 12 (33%) of the metastatic breast cancer patients remain in complete response (median follow-up, 15 months), and four of 17 (24%) refractory large cell lymphoma patients remain in complete response (median follow-up, 10 months). High-dose hydroxyurea may increase the effectiveness of standard autologous bone marrow transplantation regimens without substantially increasing toxicity.