Introduction: After β-carotene (BC) failed in clinical trials, there is evidence that BC might have harmful effects at high dosages. Hypothesis: Negative side effects might be mediated by BC breakdown products (BCBP). Within the BCBP there is a multitude of aldehydic coumpounds, which exert similar effects compared with HNE. BC is cleaved non-enzymatically by liberated oxidants of PML [1]. Supplementation of BC seems to be important in various diseases. Therefore, it is necessary to think on safe conditions expecially for high-dosage supplementation. Materials Methods: BC degradation was investigated under various conditions. BC was rapidly degraded by PML, too. Hepatocytic mitochondrial respiration and genotoxicity were evaluated in presence of BCBP. In parallel experiments antioxidants such as alpha-tocopherol, ascorbic acid, uric acid etc. were used to avoid negative side effects. Results: BCBP modify the activities of enzymes and transport proteins such as Na-K-ATPase, NADPH oxidase, and adenine nucleotide translocator. At nanomolar concentrations BCBP exert genotoxic effects [2,3]. BCBP impair mitochondrial functions at low mikromolar concentrations [4,5]. During incubation of mitochondria with BCBP GSH and protein SH decreased, GSSG and MDA increased. PML mediated BCBP formation was reduced in presence of antioxidants. The inhibition of ADP-stimulated respiration was also mitigated in presence of antioxidants. Discussion Conclusions: The data indicate a basic pro-oxidative mechanism of high concentrated BC at heavy oxidative stress leading to rapid formation of BCBP. Antioxidants mitigate potential toxic effects [6]. References: [1] Sommerburg O Free Radical Biol Med 35, 1480 (2003). [2] Alija A Cancerogenesis 25, 827 (2004). [3] Alija A Cancerogenesis 27, 1128 (2006). [4] Siems W FASEB J16, 1289 (2002). [5] Siems W J Nutr Biochemistry 16, 385 (2005). [6] Siems W 3^rd ISNA, Medimond, pp. 61 (2005).