Associations between metabolic syndrome (MS) and major depressive disorder (MDD) are well documented although the underlying biological mechanisms for this relationship are less studied. Paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme, with demonstrated evidence of strong antioxidant activity. Oxidative stress has been implicated in the pathophysiology of MS and MDD. PON1 activity has been studied to some extent in patients with MS and less in MDD. The aim of this study was to compare serum PON1 activity in patients with MS and MDD, MS without MDD, and normal control groups in the context of the biological mechanism of the association between MS and MDD. In this case-control study, 67 patients with MS and 25 healthy controls from the hospital-university staff were recruited. All patients and healthy controls were assessed by a semi-structured psychiatric interview. Patients with MDD were diagnosed according to the DSM-IV criteria for MDD. Serum PON1 activity was determined with a spectrophotometric method, and the activity was compared between patients with MS and MDD, with MS but without MDD, and control groups. Serum PON1 activity levels were lower in patients with MS and MDD group compared to those in the patients with MS and without MDD group and control group (69.5+/-24.2, 84.3+/-34.6, and 97.1+/-40.8 U/ml, p=0.03, respectively). Post hoc analysis showed that PON1 activity was statically significantly lower in the MS with MDD group than in the control group (p=0.02). Impaired PON1 activity, in the context of enhanced oxidative stress, could be one of the possible underlying biological mechanisms of the MS-MDD association.