Objective:To detect changes of neural response on happy facial expressions in first-onset major depressive disorder(MDD)by antidepressant treatment investigated with functional magnetic resonance imaging (fMRI). Methods:Thirteen patients with first onset MDD and 14 normal age-matched volunteers underwent fMRI and patients underwent scanning twice during an 8-week period. Blood oxygenation level dependent(BOLD) was processed using SPM2 to compare the function of whole brain between the two groups exposure to neutral and positive pictures. Results:Decreased activation of left laterial superior frontal cortex exposure to happy pictures was found in patients compared with control group(P < 0.001,uncorrected). Symptomatic improvement after antidepressant was associated with reversion of left laterial superior frontal cortex(P < 0.001,uncorrected). Conclusion:Changes in BOLD of fMRI associated with symptomatic improvement indicate that fMRI may be a useful marker of antidepressant treatment response.