Purpose: To explore antidepressant effect on the microstructural integrity of white matter (WM) by diffusion tensor imaging (DTI) in patients with first-episode major depressive disorder (MDD). Methods: In this prospective study, we recruited 32 first-episode patients who met the criteria of the Fourth Edition of Diagnostic and Statistical Manual of Mental Disorders for MDD and 35 age- and sexmatched healthy controls. Brain DT! was used to determine fractional anisotropy (FA) in preselected WM regions before and after the patients received sertraline for 12 weeks. The severity of depression was evaluated using the 17-item Hamilton Depression Rating Scale (HDRS). Results: Only 11 patients (34.38%) completed post-treatment MRI exam. Patients with MDD displayed lower baseline FA values, predominantly in bilateral upper frontal WM at 10mm above the anterior commissure-posterior commissure (AC-PC) plane, than healthy controls. The correlation between baseline HDRS scores and FAvalues was inversely significant in left lower frontal WM at 10mm below the AC-PC plane. After treatment, FA values significantly increased in bilateral upper frontal WM at 10mm above the AC-PC plane. Conclusion: Antidepressants administered for 12 weeks to first-episode MDD patients increase FA values .WM microstructure subnormalities may develop early in the course of the illness.