Depression is a risk factor for coronary heart disease (CHD). It has been demonstrated that there is a potential role of nitric oxide (NO) in the relationship between depression and CHD risk as well as an effect of antidepressants on NO production. This study included 40 in- or outpatients in our university hospital who met the DSM-IV-TR criteria for major depressive disorder (M/F: 15/25, age: 47+/-19 years) and 30 age- and sex-matched healthy controls (M/F: 10/20, age: 45+/-15 years), and also examined the effects of the antidepressants on the plasma NOx levels in depressed patients. The baseline plasma NOx levels were significantly lower in the whole depressed group than in the control group (p<0.01). Treatment with milnacipran, but not paroxetine, significantly increased the plasma NOx levels by 4 and 8 weeks. These results suggest that decreased plasma NOx levels might be partially associated with the pathophysiology of depression, and that treatment with milnacipran, a serotonin noradrenaline reuptake inhibitor, might increase those levels in depressed patients.