The purpose of this study was to examine the relationship between personality and depression in a general population in relation to gender and age. The Nord-Trøndelag Health Study (2006-2008), a large cross-sectional survey, was used. The sample consists of 35,832 men (16,104) and women (19,728) aged 20-89 years, living in the Nord-Trøndelag County of Norway, with valid ratings on the depression subscale of the Hospital Anxiety and Depression Scale (HADS) and Eysenck Personality Questionnaire (EPQ). This study demonstrates a relationship between depression and both neuroticism and extraversion in a general population. Older people score low more often on Extraversion (E) than younger people. Interactions were observed between neuroticism and age, gender, and extraversion with depression. The interaction term indicates a high score on Neuroticism (N) enhanced by introversion, older age, and being a male with depression. The findings suggest that health professionals may need to put extra effort into the care of patients with low extraversion and high neuroticism, in order to help those patients avoid depression.