To compare therapeutic efficacy, social function, discontinue rate, relapse and recurrence rate of the depression outpatients with first episode between Venlafaxine extended release and Fluoxertine hydrochloride treatment. Methods In this 48 week natural parallel follow-up study, total 188 patients who meet ICD-10 criteria for a major depressive episode were admitted and assigned to receive either Venlafaxine Extended Release (Venlafaxine XR group) (n=89) or Fluoxertine hydrochloride(Fluoxertine group) (n=99).At baseline,week2,8,12,16,24,32,48,Hamilton Rating Scale for Depression (HAMD)-17 item was used to value disease severity, and Social Disability Screening Schedule(SDSS)for social disability, and the discontinue, relapse and recurrence rates were compared. Results (1) At week 24 Venlafaxine XR group had much lower HAMD17 total score than Fluoxertine group (P<0.05). (2)The remission rate and response rate between two groups had no statistical difference (P>0.05). (3) At week 12, Venlafaxine XR group had a higher SDSS score than Fluoxertine group (P<0.05).(4)At week 12, 16, 24, 32,48,Venlafaxine XR group displayed lower discontinue rates (P<0.05). Venlafaxine XR group had a longer treatment course than Fluoxertine did [(30.99±15.98) weeks vs. [(22.57±15.26) weeks] (P<0.01). (5) The relapse and recurrence rates of two groups had no statistical difference (P>0.05). Conclusions In the acute phase, Venlafaxine XR has a better effect for social function and treatment adherence than Fluoxertine hydrochloride. In the continued phase and sustained phase, Venlafaxine XR performs better for symptoms relief and treatment adherence.Venlafaxine XR has parallel performance with Fluoxertine hydrochloride by the terms of therapeutic efficacy, social function restore, relapse and recurrence rate.