BACKGROUND: The association between personality traits and the first lifetime onset of clinically significant depression has not been studied in older adults. METHOD: Experienced psychiatrists conducted interviews and chart reviews at baseline and throughout the 15-year follow-up period. Survival analyses were conducted on the presence/absence of a DSM-III-R mood disorder at follow-up. RESULTS: There were 59 cases of first lifetime episodes of depression. Analyses showed that Neuroticism [hazard ratio (HR) per one point increase in the Maudsley Personality Inventory (MPI)=1.05, 95% confidence interval (CI) 1.02-1.08] but not Extroversion (HR 1.02, 95% CI 0.97-1.06) amplified risk for mood disorder. CONCLUSIONS: This prospective study on a randomly sampled birth cohort of older adults showed that Neuroticism confers risk for a first lifetime episode of clinically significant depression. Findings have implications for understanding the etiology of late-life depression (LLD) and could also aid in the identification and treatment of people at risk.