The purpose of this study was to estimate the response rate, response duration, and survival of patients with advanced ovarian cancer treated with a 132-hr continuous infusion of high-dose calcium leucovorin in combination with five consecutive daily bolus doses of 5-fluorouracil (5-FU) and to correlate changes in CA-125 levels with clinical and radiologic assessment of disease progression. Forty-six heavily pretreated patients [median number of previous chemotherapy regimens, 2.5 (range 1-7)] with advanced ovarian cancer received 132-hr continuous infusions of calcium leucovorin (500 mg/m2/day) for 5 1/2 days, with daily bolus doses of 5-FU (370 mg/m2/day) for 5 days beginning 24 hr after initiation of the calcium leucovorin. Twenty-three patients had clinically measurable disease and 23 had evaluable disease; CA-125 levels were performed prior to each treatment course and after the final course of therapy. One of 42 patients had a partial response to combination chemotherapy (duration, 8.9 months); 16/42 had stable disease [median duration, 4.9 months (range, 2.4-9.0 months)]. Toxicity of combination therapy included mild myelosuppression and stomatitis, similar to previously reported toxicity profiles for the 5-FU and calcium leucovorin combinations. Sensitivity of CA-125 levels as a single indicator of disease progression was 55%. The combination of infusional high-dose calcium leucovorin and 5-FU has little activity in refractory ovarian cancer. CA-125 levels incorrectly predict clinical disease activity in about one-third of cases and should not be the sole criterion for determination of clinical response when evaluating chemotherapeutic efficacy in heavily pretreated patients.