Objective: 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. Methods: Forty-seven overweight men and women (body mass index 26-43 kg/m2 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. Results: 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. Conclusions: 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.