Purpose. To test whether a higher sodium dose in the hydration solution may facilitate faster methotrexate (MTX) elimination as compared with a lower sodium dose following high-dose MTX (HDMTX) treatment. Methods. Intravenous solutions with alternate doses of sodium (regimen A 70mEq/l, regimen B 100mEq/l) were given to 30 children with acute lymphoblastic leukemia in two courses of HDMTX in a randomized crossover fashion. The plasma MTX concentrations every 24h from the beginning of MTX administration and the adverse events associated with HDMTX were compared between the two hydration regimens. Results. The plasma MTX concentrations were similar in the two hydration regimens at 24h (A 50.97.4 vs B 40.95.4M, means SE, P=0.17), but was significantly lower in regimen B at 48 and 72h (A 0.650.17 vs B 0.270.03M, P=0.04; and A 0.140.03 vs B 0.050.01M, P=0.003). The time during which MTX plasma concentrations exceeded 0.1M was significantly longer in regimen A than in regimen B (A 3.830.18 vs B 3.130.06days, P=0.001). The incidences of adverse events were similar between the two regimens (P=0.78), and severe adverse events were not seen in either regimen. Conclusions. Hydration with a higher sodium dose facilitated faster MTX elimination following HDMTX. Sodium may have a beneficial effect on MTX-induced nephrotoxicity.