5-fluorouracil (5-FUra) and etoposide demonstrate relationships between schedule of administration and activity in a number of clinical situations. With limited information regarding 5-FUra and oral etoposide in sarcoma, and informal observations suggesting activity of infusional 5-FUra in sarcomas, a phase II study was performed. This phase II study attempted to evaluate the efficacy of the combination of low-dose continuous infusion 5-FUra (LDCI-5FUra) and oral etoposide administered to patients with advanced sarcomas. Treatment consisted of 5-FUra at 300 mg/m2/day and etoposide at 50 mg/m2/day for 21 days. Cycles were repeated at 28-day intervals or upon recovery from toxicity. Twenty patients received 50 cycles of therapy. No objective responses were seen in 19 evaluable patients (response rate 0%, 95% confidence interval 0-18%). Toxicity was mild and consisted primarily of stomatitis, diarrhea, and leukopenia. Median survival for all patients was 9 months (1.8-30+ months range). The combination of LDCI-5FUra and oral etoposide, at the doses and schedule studied, was inactive in this population with advanced sarcoma.