The pharmacokinetics of SH‐methotrexate were studied in 22 patients with malignancies. Following the intravenous administration of 30 mg methotrexate (Mtx) per square meter, the plasma disappearance was triphasic with half‐lifes of 0.7.5 ± 0.11,3.49 ± 0 . .55, and 26.99 ± 4.44 hours, respectively. The urinary excretion of radioactivity paralleled the plasma data for most patients. A metabolite was found in urine that eluted before Mix when chromatographed on a diethylaminoethyl (DEAE) cellulose column. The excretion of this metabolite reached steady state and accounted for 20 (14 to 37) per cent of the radioactivity in urine after 30 hours. Our observation that Mtx has a long terminal half‐life may explain the high incidence of tOXicity in patients receiving chronic low‐dose Mtx therapy.