Objective: To identify target groups for prevention of chronic or recurrent depression in old age such that prevention is likely to become cost-effective. Methods: Data were used from a population-based cohort study (N = 2,200). Chronic or recurrent depression was defined when people presented with clinically high levels of depression at two time points separated by 3 years. Risk profiles of these conditions were identified using classification and regression trees analysis. The combinations of risk factors were then evaluated in multivariate models to ascertain their utility for preventing depression in high-risk groups. Results: People are placed at a high risk of depression when having symptoms of anxiety, functional impairments, two or more chronic illnesses, and either a low attained educational level or below average levels of mastery, while living without a partner. These risk profiles correspond with groups no larger than 8.3% of the older population. Containing the adverse effects of the risk factors would help to reduce the incidence of depression by possibly as much as 48.7%, indicating that large health gains can be generated, which can also be done efficiently with numbers-needed-to-be-treated, perhaps as small as three. Conclusion: Targeting prevention on the selected high-risk groups is likely to become a cost-effective endeavor, because optimal health gains can be generated efficiently in groups small enough to be logistically manageable. The burden of illness associated with depression, particularly depression, in aging populations underscores the public health significance of such an approach. © 2008 American Association for Geriatric Psychiatry.