Objective: The mechanisms that underlie the association between abdominal obesity and depression risk in older persons are not well known, but the "leptin hypothesis" of depression suggests that leptin resistance may be involved in mood regulation. We tested whether high circulatory concentration of leptin, alone and in combination with visceral adiposity, is associated with onset of depression in a sample of older persons. Method: Participants were 1,220 men and 1,282 women aged 70-79 years and enrolled in the Health, Aging, and Body Composition study. Serum concentration of leptin and abdominal visceral fat, ascertained by computed tomography, were assessed at baseline (April 1997-June 1998). Onset of depression, the primary outcome measure, was defined as a Center for Epidemiologic Studies-Depression Scale 10-item score ≥ 10 and/or new antidepressant medication use at any annual visit over a 5-year follow-up. Results: Higher leptin level was associated with the risk of depression onset in men with high levels of visceral fat (hazard ratio [HR] = 1.25; 95% CI, 1.06-1.46; P = .01) but not in those with normal visceral fat (HR = 0.98; 95% CI, 0.80-1.19; P = .80) (leptin-by-visceral fat, P = .04). No interaction between leptin and visceral fat was detected in the analysis focusing on women (P = .90). Conclusions: In older men, high leptin level was associated with an increased onset of depressive symptoms, especially in the presence of abdominal obesity, suggesting that underlying leptin resistance may play a role in this link. Differences in visceral fat levels and metabolic consequences may explain the absence of this association in women. These findings suggest a potential biological link between depression, obesity, and their joint association with negative health outcomes. © Copyright 2012 Physicians Postgraduate Press, Inc.