Cross-sectional studies show associations between depression and endothelial function (as measured by endothelium-dependent brachial artery flow-mediated dilatation [FMD]); but it is not known whether changes in these parameters are associated following dietary management. We have previously reported that compared with consumption of a high-carbohydrate (HC) diet, despite comparable weight loss, a very low-carbohydrate (LC diet) impaired FMD and increased depression. The purpose of this study was to conduct a secondary analysis to examine whether there was an association between changes in FMD and depression.Forty-seven overweight men and women (body mass index 26-43 kg/m(2) and ages 24-64 y) completed a 12-mo randomized controlled trial during which participants consumed either an energy-restricted, isocaloric LC or HC diet. Weight, body composition, Homeostasis Assessment of Insulin Resistance (HOMA), depression (Beck Depression Inventory [BDI]), Anxiety (Spielberger State-Trait Anxiety Inventory [STAI]) and FMD were assessed before and after the intervention. This secondary analysis focused on multiple regression analysis of these parameters.Changes in BDI were independently predicted by changes in FMD (β = -0.356; P = 0.026) but not by diet intervention assignment or changes in weight or HOMA. No variables were significant predictors of the change in STAI.Over time, impairments in FMD were independently associated with increased depression, independent of diet composition, or changes in weight and insulin resistance. This data supports a mechanistic association between depression and endothelial function, which may influence long-term health.