Abstract There is considerable evidence that cardiovascular diseases are more prevalent in patients with major depressive disorder (MDD). Secretion of N-terminal pro-B-type natriuretic peptide (NT-proBNP) increases in several cardiac illnesses, making this neurohormone a reliable diagnostic and prognostic biomarker of cardiovascular risk. We measured plasma NT-proBNP levels in the following three groups of subjects free of overt cardiovascular disease: unmedicated patients with MDD ( n = 40), unmedicated patients with schizophrenia ( n = 44), and normal control subjects ( n = 42). The severity of depressive symptoms was rated using the Hamilton Depression Rating Scale (HAMD). Plasma NT-proBNP levels were assayed by ELISA. Plasma NT-proBNP levels were significantly higher in the MDD group (median: 217.1 pmol/L; interquartile range: 179.4–277.1 pmol/L) than in patients with schizophrenia (175.7 pmol/L [139.0–218.9]; P < 0.05) or in the control group (158.9 pmol/L [98.3–212.1]; P < 0.001). Among patients with MDD, there was a significant positive correlation (Spearman's rank correlation = 0.422, P = 0.008) between plasma NT-proBNP and HAMD scores. Altogether, our results indicate that elevated NT-proBNP levels may play a role in linking MDD with increased cardiovascular risk.