AbstractMajor depressive disorder (MDD) is associated with immunologic and metabolic alterations linked to central processing dysfunctions, including attenuated reward processing. This study investigated the associations between inflammation, metabolic hormones (leptin, insulin, adiponectin), and reward-related brain processing in MDD patients with high (MDD-High) and low (MDD-Low) C-reactive protein (CRP) levels compared to healthy comparison subjects (HC). Participants completed a blood draw and a monetary incentive delay task during functional magnetic resonance imaging. Although groups did not differ in insulin or adiponectin concentrations, both MDD-High (Wilcoxon p = 0.004, d = 0.65) and MDD-Low (Wilcoxon p = 0.046, d = 0.53) showed higher leptin concentrations than HC but did not differ from each other. Across MDD participants, higher leptin levels were associated with lower brain activation during reward anticipation in the left insula (r = − 0.30, p = 0.004) and left dorsolateral putamen (r = -− 0.24, p = 0.025). In contrast, within HC, higher leptin concentrations were associated with higher activation during reward anticipation in the same regions (insula: r = 0.40, p = 0.007; putamen: r = 0.37, p = 0.014). Depression may be characterized by elevated pro-inflammatory signaling via leptin concentrations through alternate inflammatory pathways distinct to CRP.