Pipecolic acid (PA) levels are increased in severe metabolic disorders of the central nervous system such as Zellweger syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy and hyperlysinemia. The affected individuals present progressive neurological dysfunction, hypotonia and growth retardation. The mechanisms of brain damage of these disorders remain poorly understood. Since PA catabolism can produce H2O2 by oxidases, oxidative stress may be a possible mechanism involved in the pathophysiology of these diseases. Lipoic acid (LA) is considered an efficient antioxidant and has been shown to prevent oxidative stress in experimental models of many disorders of the neurologic system. Considering that to our knowledge no study investigated the role of PA on oxidative stress, in the present work we investigated the in vitro effects of PA on some oxidative stress parameters and evaluated the LA efficacy against possible pro-oxidant effects of PA in cerebral cortex of 14-day-old rats. The activities of catalase (CAT), glutathione peroxidase (GPx), glucose 6-phosphate dehydrogenase (G6PD), and glutathione S-transferase (GST) along with reduced glutathione (GSH) content were significantly decreased, while superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBA-RS) were significantly enhanced by PA. LA was able to prevent these effects by improving the activity of antioxidant enzymes, increasing GSH content and reducing TBA-RS. In contrast, glutathione reductase and 6-phosphogluconate dehydrogenase activities and sulfhydryl content were not affected. Taken together, it may be presumed that PA in vitro elicits oxidative stress and LA is able to prevent these effects.