Objective: Despite the adequate time and dose of antidepressant treatment, approximately one-third of the patients with major depression do not respond. In previous trials, mirtazapine combination was found to be efficacious in treatment-resistant depression which is non-response to two previous adequate antidepressant drug treatments from different classes. In this present study, it is aimed to assess the efficacy and the tolerability of mirtazapine combination treatment in patients with treatment-resistant major depression by retrospective chart review.Method: During the period between August 2004 and July 2005, all the charts of the patients with treatment resistant major depressive disorder were selected. For the assessment, Hamilton Depression Rating Scale (HAM-D) and Clinical Global Impression (CGI) were used. For the assessment of adverse effects, the report of the patients was considered. Forty-three in- or outpatients with major depression who previously received two antidepressants of different groups and did not respond (<50% of symptom reduction in HAM-D) to either treatment were assessed. Of the 43 patients who fulfilled the inclusion criteria, 39 patients had complete data for the assessment. The study was based on the chart records of 39 patients. At the time of assessment, 18 (41.9%) patients were receiving venlafaxine, and 25 (58.1%) patients were receiving an SSRI (15 on citalopram, 6 on sertraline, and 4 on paroxetine).Result: The mean age of the study group was 42.2±12.9, and 74.4% (n=32) female. Of the whole sample, 14 (32.6%) patients were having their first episode, whereas 29 (67.4%) patients had a recurrent major depression. Ten (23.3%) patients were inpatients and 33 (76.7%) patients were outpatients. The mean HDRS score was decreased from 23.1±5.1 to 7.3±5.6 at the end of the assessment of six weeks, and 21 (53.8%) patients achieved remission (HDRS<7). When the primary antidepressant was taken into consideration, patients on venlafaxine had significantly more remission rate compared to patients on selective serotonin reuptake inhibitors (SSRI). In 27.9% (n=12) of the patients, adverse events were emerged, and weight gain was predominant with 8 patients. In two patients who were dropped out due to adverse events, one patient experienced weight gain (8 kg/4 weeks) and the other had anxiety and agitation.Discussion: Mirtazapine combination treatment is an efficacious and well-tolerated alternative in treatment-resistant major depression. When the primary antidepressant is venlafaxine, this combination therapy seems to be more effective.