1. Morphine has been shown to slow the renal excretion of other drugs. The present study in mice evaluated the effects of morphine on the disposition of methotrexate (MTX), an antimetabolite eliminated by the kidneys. 2. Mice were injected with morphine (20 mg/kg) or saline s.c. After 30 min, 20-80 mg/kg MTX was injected i.v. Blood and urine samples were assayed for MTX by HPLC. 3. Morphine reduced plasma clearance (CL) of MTX from 0.147 +/- 0.015 to 0.061 +/- 0.009 mL/min per g bodyweight (P < 0.01). The area under the plasma concentration-time curve (AUC(0- infinity )) was raised by morphine from 151 +/- 18 to 369 +/- 36 micro g.mL per min (P < 0.01). Without morphine administration, 22-27% of an MTX dose was excreted into the urine in 30 min. The corresponding fractions excreted into the urine after morphine were reduced to 15-18% (P < 0.01). 4. Plasma levels of MTX administered intravenously to mice are elevated by the concomitant administration of morphine, which reduces renal elimination of MTX.