The disposition of morphine in the serum and in the cerebral cortex during normocarbia and hypocarbia was studied in dogs. Normocarbia was maintained by controlled ventilation with air (pHa, 7.40; Paco2, 40 torr) and by controlled hyperventilation with a gas mixture of CO2, 3 per cent, O2, 21 per cent, balance N2 (pHa, 7.40; Paco2, 38 torr). Hypocarbia was induced by hyperventilation with air (pHa, 7.57, Paco2, 20 torr). After achievement of a steady acid-base status, morphine sulfate, 2 mg/kg, was injected intravenously. Thereafter, serial samples of serum and cerebral cortex were taken at intervals for four hours and analyzed for morphine concentrations using radioimmunoassay. In dogs with hypocarbia, serum morphine concentrations 15-240 min following intravenous injections were higher; the serum half-life during the elimination phase remained unchanged, 62-65 min. The apparent volume of distribution, Vd and plasma clearance, Clp of morphine were less during hypocarbia. Morphine concentrations in the cerebral cortex were significantly increased at 15-240 min during hypocarbia. Estimated half-lives of morphine in the cerebral cortex were 5.5 hours during normocarbia, and 8.2 hours during hypocarbia. Maintenance of normocarbia during hyperventilation minimized these changes. These results suggest that during hypocarbia the higher serum morphine concentrations, higher drug distribution coefficient in lipid phase and increased ratio of free base: acid salt of morphine facilitated the penetrance of morphine into the brain, in spite of decreased cerebral blood flow. Once in the brain, a greater portion of morphine was probably present in the protonated form in a relatively acidic milieu and thus less able to pass through lipid barriers back to the circulation.