Dopamine and serotonin were determined in extracellular fluid of rat striatum by semiderivative in vivo voltammetry during normoxia and a single or repeated exposure to 15% O2 (i.e., mild hypoxia) or 12.5% O2 (i.e., moderate hypoxia). A single exposure to 15% oxygen increased extracellular dopamine 76%. With reintroduction of air to the animals, dopamine values returned to baseline. During a second episode of 15% oxygen, dopamine increased 63% and remained elevated even during a final exposure to air. On the other hand, serotonin was unaffected by 15% oxygen. Moderate hypoxia (12.5% oxygen) increased dopamine (79%) and serotonin (26%) and both remained elevated even after the initial reintroduction of air. These studies demonstrate that in vivo hypoxia increases rat striatal extracellular dopamine and, to a lesser extent, extracellular serotonin. Furthermore, after repeated, mild hypoxic episodes or moderate hypoxia, the increases in rat striatal extracellular dopamine and serotonin continue even during normoxia. These studies further support a role for dopamine and serotonin in hypoxic-induced changes in brain function. The hypoxic-induced elevation of these two neurotransmitters during normoxia may be important in the production of hypoxic/ischemic-induced cell damage.