Objective: Although the second-generation antipsychotic, aripiprazole (ARI), has been approved as an adjunct for treatment-resistant major depressive disorder (MDD), neither ARI nor any second-generation antipsychotic has been assessed in combination with an antidepressant at the initiation of a treatment trial for non-treatment-resistant MDD. The aim of the present study was therefore to assess the safety, tolerability, and remission rate in the treatment of MDD using the specific combination of venlafaxine-XR (VEN-XR) and ARI in a generalizable, difficult-to-treat group with chronic or recurrent MDD. Methods: Self-declared participants in primary care or psychiatric settings who had chronic or recurrent MDD and a minimum score of 14 on the 17-item Hamilton Rating Scale for Depression were included. Up to 12 weeks of open treatment with the combination of VEN-XR and ARI was provided. Participants began with VEN-XR, and ARI was added at week 2. Maximum allowable doses were 300 mg day 1 for venlafaxine-XR and 30 mg day1 for ARI. Remission was defined as ≤ 5 on the 16-item Quick Inventory of Depressive Symptomatology Self-report (QIDS-SR16). Results: Fifty outpatients with non-psychotic MDD were enrolled (mean age = 43±11 years; 38% male; QIDS-SR16=15±3). Mean exit dose of VEN-XR was 227±97 mg day1, and the mean exit dose of ARI was 11±7 mg day1. The combination was well tolerated; 16% of participants discontinued due to side-effects. Approximately 70% achieved remission at some point during the trial, and 66% achieved remission at study exit. Conclusions: To the best of the authors' knowledge this is the first study to combine an antidepressant and second-generation antipsychotic at the beginning of a treatment trial for chronic or recurrent non-treatment resistant MDD. VEN-XR and ARI combination appears to warrant further study in controlled trials. © 2009 Informa UK Ltd All rights reserved.