Mood-related phenotypes are commonly comorbid with, and have been implicated in the development of, neurological disorders. APOE is a major susceptibility gene for neurodegeneration. Recent evidence from case-control studies has suggested that the apoE 2 allele is associated with major depressive disorder (MDD). However, evidence from large-scale community-based studies is limited. APOE was genotyped for 17,507 men and women, aged 41-80 years, participating in the European Prospective Investigation into Cancer-Norfolk study, who had also completed a psychosocial assessment that included measures of emotional health status defined by MDD, psychological distress (as represented by the Mental Health Inventory, MHI-5), and by an assessment of neuroticism. No associations were found between APOE genotypes and measures either of past-year or lifetime MDD, or of emotional health defined according to the MHI-5 or by neuroticism. Data from this large-scale, community-based, study are not supportive of an association between either MDD or associated measures of emotional state and APOE genotype. These findings suggest that the association between APOE and MDD risk is more modest than has been previously reported.