Inflammation-related changes in the concentrations of kynurenine-pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid, KA) and neurotoxic (3-hydroxy-kynurenine, 3HK and quinolinic acid, QA) kynurenine-pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. Twenty-nine moderately-to-severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided a blood sample for kynurenine metabolite analysis, performed using high performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori-defined variable of interest, the KA/QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. Post-hoc data reduction methods yielded 3 principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, while component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.Neuropsychopharmacology accepted article preview online, 30 July 2014; doi:10.1038/npp.2014.194.