The addition of leucovorin to 5-fluorouracil (5-FU) has been shown to improve the response rate in recurrent colon cancer. The combination of low-dose leucovorin and 5-FU was previously tested by the Gynecologic Oncology Group (GOG) and did not produce response rates greater than rates using 5-FU alone. From June 1990 to April 1992, 55 patients with unresectable recurrent squamous cervical cancer received high-dose leucovorin at 200 mg/m2 i.v. bolus, followed by 5-FU at 370 mg/m2 i.v. bolus daily for 5 days every 4 weeks for the first two courses. Subsequent courses were given every 5 weeks. The median number of courses delivered was two (range 1-15). Fifty patients were evaluable for toxicity and 45 for response. Prior radiotherapy had been given to 43 patients and prior chemotherapy to 38. The overall response rate was 8.8% (95% confidence interval, 2.5-21.2%). There were two complete responses (4.4%) and two partial responses (4.4%). One response was in the pelvis and three were outside the pelvis. None of the extrapelvic responses had received irradiation at the site of measurable disease. The major adverse effect was granulocytopenia, with 15/50 (30%) experiencing GOG grade 3 or 4 granulocytopenia. The median white blood count for patients experiencing leukopenia was 2,000 (range 400-3,800). Grade 3 or 4 gastrointestinal toxicity was seen in 12 patients (24%). In this pretreated population, patients receiving high-dose leucovorin with 5-FU had moderate toxicity but only minimal activity.