Hyperoxemia is known to alter tissue oxygenation, which in the brain results in a scattered and an uneven distribution of cerebrocortical tissue oxygen pressures (PtO2). This study examined the effect of ritanserin (a highly specific serotonin receptor antagonist, 5-HT2) on the PtO2 distribution during hyperoxemia. The measurements of brain oxygenation were performed on the motor cortex in anesthetized pigs with a multiwire Clark-type microelectrode. Ritanserin was administered (0.035 mg/kg i.v.) during hyperoxemia (inspired oxygen fraction = 0.70). In 4 of 5 animals, the disturbed oxygenation that was registered during hyperoxemia was normalized after the ritanserin injection. These results indicate that serotonin may be involved in the regulation of brain oxygenation during hyperoxemia, and they also suggest that serotonin may be a link in the coupling between the oxygen metabolism and the regulation of blood flow in the brain.