A total of 45 courses of 50 g (24 to 33 g/m2) of high-dose methotrexate (HDMTX) followed by an improved citrovorum rescue (CFR) were administered to 23 patients according to a recently updated procedure. All patients previously had received HDMTX-CFR at lower doses. The HDMTX was administered intravenously (IV) over 6 hours with a priming dose of 8 g followed by 42 g given by continuous infusion. Maintenance of adequate urine output and pH level were achieved with IV fluids, sodium bicarbonate, oral acetazolamite, and a low-acid diet. The CFR was administered by following the equimolar rescue technique and was continued until the serum MTX level was less than 2 X 10(-7) mol/l. The MTX was usually rapidly cleared. The median 48-hour serum MTX level was 7.57 X 10(-6) mol/l (range, 6.8 X 10(-7) mol/l to 7.9 X 10(-5) mol/l). Most patients cleared MTX to below 10(-7) mol/l by the eighth day (range, 5 to 13 days) after MTX infusion. The MTX clearance did not always correlate with the pretreatment creatinine clearance. The toxicity observed included the following: leukocyte count less than or equal to 2000/microliters in 11% of the courses with less than or equal to 1000/microliters in 0%, platelets less than or equal to 10(5)/microliters in 9%, creatinine elevation to greater than or equal to 1.5 mg/dl in 7%, mild mucositis without ulcerations in 33%, nausea with occasional vomiting in 66%, mild skin rash in 18%, and temporary elevation of liver enzymes in 81% of the courses. All side effects were tolerable and transient, and the patients recovered fully. Patients who cleared MTX rapidly (MTX less than or equal to 2 X 10(-6) mol/l at 48 hours) rarely sustained leukopenia, creatinine elevation, or skin rash. Toxicity was not increased by third space fluids or by delaying CFR to 24 hours instead of 12 hours after MTX. The procedure described allows the safe administration of HDMTX-CFR at the 50-g range to adults with advanced malignant solid tumors.