Perinatal hypoxia-ischemia remains a significant cause of neonatal mortality and neurodevelopmental disability. Numerous lines of evidence indicate that cerebral ischemic insults disrupt normal respiratory activity in mitochondria. Carnitine (3-hydroxy-4-N-trimethylammonium-butyrate) has an essential role in fatty acid transport in the mitochondrion and in modulating potentially toxic acyl-CoA levels in the mitochondrial matrix. There are no naturally occurring esterases available to reduce the accumulation of acyl-CoA but this process can be overcome by exogenous carnitine. We used a newborn rat model of perinatal hypoxia-ischemia to test the hypothesis that treatment with l-carnitine would reduce the neuropathologic injury resulting from hypoxia-ischemia in the developing brain. We found that treatment with l-carnitine during hypoxia-ischemia reduces neurologic injury in the immature rat after both a 7- and 28-d recovery period. We saw no neuroprotective effect when l-carnitine was administered after hypoxia-ischemia. Treatment with d-carnitine resulted in an increase in mortality during hypoxia-ischemia. Carnitine is easy to administer, has low toxicity, and is routinely used in neonates as well as children with epilepsy, cardiomyopathy, and inborn errors of metabolism. l-Carnitine merits further investigation as a treatment modality for the asphyxiated newborn or as prophylaxis for the at-risk fetus or newborn.