Experimental studies have demonstrated that the combined effects of methotrexate and 5-FU may be optimized in schedules of administration where the antifolate is administered prior to the fluoropyrimidine. Seventeen patients with ovarian carcinoma refractory to standard chemotherapy were treated with a sequence of moderate dose MTX (200 mg/m2) and 5-FU. No responses were seen, although the hematologic and gastrointestinal toxicity which was observed was very mild. Because of prior nephrotoxic chemotherapy and the frequent presence of large amounts of "third space" fluid in the form of malignant ascites, patients with ovarian cancer are at high risk for MTX toxicity. In this study, eight patients with significant ascites had higher plasma MTX concentrations measured at 48 and 72 hr following drug administration than nine similar patients without ascites. This suggested delayed excretion of MTX in patients with ascites although this difference was not statistically significant. MTX concentrations in ascites exceeded those in plasma between 6 and 12 hr and remained near 1 microM for 24 hr. Although the lack of response is disappointing, the modest toxicity encountered with the careful drug level monitoring and the favorable pharmacologic findings suggest that this combination of drugs each with established activity in untreated ovarian cancer deserves further study in primary treatment.