In recent years there has been increasing evidence of an inflammatory component due to overstimulation of the hypothalamic-pituitary-adrenals (HPA) in depression. The glutamate metabolites (glutamate and glutamine) are important metabolites that are involved in this stimulation. The aim of this study was to determine the concentrations of hypothalamic glutamate metabolites in depression and to investigate their relationship to peripheral inflammation. Participants with diagnosed depression (DE; n = 24) and control subjects without depression (HC; n = 25) were investigated. Hypothalamic glutamate metabolites were recorded using in vivo magnetic resonance spectroscopy. Peripheral cytokines (IL-6, TNF-α, IFN-γ and IL-1β) were assessed using Enzyme-Linked Immunosorbent Assay. For statistical analysis, generalized mixed models were computed using Poisson distributions and a log link function. The results show overall higher hypothalamic glutamate metabolites in DE compared to HC. High TNF-a and IL-1ß concentrations are associated with high hypothalamic glutamate metabolites in DE. These results provide initial evidence that, in depression, increased HPA axis activity is associated with peripheral inflammation favored by hypothalamic glutamate metabolites.