Twenty-two patients with metastatic colorectal carcinoma were treated in a Phase I-II study of combination therapy with 5-fluorouracil (5-FU) and etoposide (VP-16). Treatment consisted of weekly intravenous VP-16, 100-120 mg/M2, followed by 5-FU, 400-480 mg/M2, in 28-day cycles. Myelosuppression was the dose-limiting toxicity with a mean nadir leukocyte count of 3,600/mm3 and a mean nadir thrombocyte count of 101,000/mm3. There were no episodes of sepsis or bleeding. The tolerable dose for this regimen is VP-16, 110 mg/M2, and 5-FU, 440 mg/M2, weekly. A total of 63 cycles of chemotherapy were given. Although 10 patients had stabilization of disease, no partial or complete responses were documented. We conclude that there is no clinical support for the in vitro synergy observed with this combination. Further trials of this combination using this schedule in colorectal carcinoma are not indicated.