Apolipoprotein E (apoE) belongs to a large heterogeneous family of lipid-binding proteins and is produced by a variety of tissues including the brain and liver where it subserves a diversity of functions. The primary metabolic role of apoE is as a key regulator of cholesterol and triglyceride transport between cells. It has three isoforms, E2, E3 and E4, and genetic variation in the distribution of these isoforms are associated with plasma lipid levels and atherosclerosis; the E4 isoform is also associated with increased risk for Alzheimer's disease, impaired cognition and decreased neurite outgrowth. As both lipid metabolism and synaptic connectivity are disturbed in schizophrenia and bipolar disorder, the role of apoE has been investigated in these disorders. The majority of studies have focused on the association between the genetic polymorphisms of apoE and schizophrenia with inconsistent results; however, measurement of protein apoE levels in the brain report changes in both disorders. We report here the first study to our knowledge of measurement of plasma apoE levels in subjects with schizophrenia and bipolar disorder in a medication-free state and following 6 weeks of treatment. In both medication-free schizophrenia and bipolar disorder subjects, plasma apoE levels were significantly decreased compared with control subjects and although there were increases in both groups following treatment, levels were still significantly less than for the control group. These results will be discussed in reference to their implications for altered lipid metabolism in these two disorders and the potential for the development of therapeutics to rectify these deficits leading to improved health outcomes for people with schizophrenia and bipolar disorder.