The kinetics and distribution of methotrexate in intraventricular and intrathecal cerebrospinal-fluid spaces were studied in patients with meningeal leukemia and meningeal carcinomatosis after drug administration by intravenous infusion, indwelling intraventricular subcutaneous reservoir (Ommaya), or standard lumbar puncture. Negligible ventricular concentrations followed a single intravenous dose. During an intravenous infusion (500 mg per square meter for 24 hours) the ventricular cerebrospinal-fluid concentration rose to 6 times 10-minus 7 M. Methotrexate administered by Ommaya reservoir, at a dose of 6.25 mg per square meter, rapidly distributed in the subarachnoid space; the peak ventricular concentration of 2 times 10-minus 4 M declined exponentially over 48 hours. Lumbar cerebrospinal-fluid concentration reached a maximum of 5 times 10-minus 5 M four hours after injection and then fell exponentially. Administration by lumbar puncture occasionally produced epidural and subdural leakage; even with successful lumbar puncture, ventricular methotrexate concentration varied considerably from patient to patient despite similar doses. Administration by Ommaya reservoir more reliably produced adequate cerebrospinal fluid distribution than administration by lumbar puncture.