The use of leucovorin to modulate 5-fluorouracil (FUra)-mediated inhibition of thymidylate synthase has been shown both in vitro and in vivo to improve the antitumor activity of FUra. Based on the activity of this combination in previously untreated patients, we performed a study of FUra and high-dose leucovorin (HDFA) in patients with metastatic breast cancer and minimal prior chemotherapy. Patients were stratified by prior chemotherapy (or relapse within 12 months of completing adjuvant chemotherapy) versus no prior chemotherapy (or relapse at greater than 12 months since completion of adjuvant chemotherapy). FUra was given daily for 5 days at 370 mg/m2/day with HDFA, 500 mg/m2/day, beginning 24 hours before and continuing 12 hours beyond the first and last FUra doses, respectively. Two objective responses occurred among 21 patients in the pretreated group (10%; 95% confidence interval: 1-30%). Four of 36 eligible patients (11%) in the "no prior therapy group" had complete responses (95% confidence interval: 3-26%). The major toxicities were moderate leucopenia and mucositis. We conclude that FUra plus leucovorin has modest antitumor activity in metastatic breast cancer.