To explore the involvement of apolipoprotein E gene (APO E) in major depression, we studied the APO E gene polymorphism in a sample of 156 unrelated bipolar patients and 91 healthy volunteers. This population was stratified for age at onset of the affective disorder (onset before 18 years, after 45 years and between 18 and 45 years). Early onset bipolar patients with psychotic symptoms exhibited a significant increase of epsilon4 allele frequency (28.9%) compared to either other bipolar patients (13.1%, chi2 = 6.52, df = 1, P < 0.02) or controls (12.1%, chi2 = 7.01, df = 1, P < 0.01). The association between epsilon4 and early onset bipolar disorder (BPD) with psychotic symptoms suggests that APO E gene is a risk factor for a subgroup of BPD, or influences the phenotypic expression (i.e. psychotic symptoms or age at onset) of manic depressive illness.