AbstractApolipoprotein D (apoD) is a lipid binding protein expressed in the brain where its function is largely unknown. Based on changes in lipid metabolism and deposition that occur in the human brain during postnatal development, we investigated changes in apoD expression in the prefrontal cortex in 69 normal cases ranging in age from 40 days to 49 years utilizing gene microarray, quantitative PCR and western blotting methods. In contrast to the high expression of apolipoprotein E (APOE), low‐density lipoprotein receptor‐related protein 8 (LRP8) and 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reducatase (HMGCR) (genes that play a role in lipid‐related pathways in brain development) early in life, apoD expression was low in neonates and increased in expression throughout life resulting in six‐ to eight‐fold higher levels at the mRNA and protein levels in adults. Recent studies suggest that apoD has a novel antioxidant function in the brain and we found that the increased apoD expression throughout development and into adulthood was correlated with the expression of antioxidant genes superoxide dismutase 1 (SOD1) and glutathione peroxidase 3 (GPX3) as well as proteins that were modified by the lipid peroxidation end‐product 4‐hydroxynonenal. These studies reveal that apoD expression is increased throughout life in the human prefrontal cortex and that this is correlated with genetic and biochemical markers of oxidative stress.