OBJECTIVE Venlafaxine and mirtazapine in combination are increasingly used in clinical practice to treat treatment-refractory depression. Putative efficacy for this combination of antidepressants, beyond that of monotherapy, stems from their synergistic actions. This paper describes a prospective case series that examined the efficacy of the venlafaxine-mirtazapine combination in the treatment of depressed patients who had failed at least one antidepressant trial. METHODS Twenty-two depressed patients with major depression were treated with venlafaxine and mirtazapine in combination for an average of just under 8 weeks. Baseline ratings on the 17-item Hamilton Depression Rating Scale (HAM-D(17)), Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression-Severity Scale (CGI-S) were repeated at end-point, determined by the naturalistic termination of the depressive treatment episode or the discontinuation of the combination treatment due to adverse effects. The length of treatment until end-point was documented for each patient. Descriptive statistics were used on the collated data. RESULTS At baseline, mean scores were 28.8 (SD=3.8) for HAM-D(17), 30.1 (SD=5.8) for MADRS, and 4.5 (SD=0.5) for CGI-S, reflecting a cohort at the moderate to severe end of the spectrum. At end-point, mean absolute scores were 10.2 (SD=4.7) for HAM-D(17), 10.8 (SD=4.6) for MADRS, and 2.3 (SD=0.6) for CGI-S. Mean change from baseline was 18.6 (SD=6.4) for HAM-D(17), 19.3 (SD=6.8) for MADRS, and 2.3 (SD=0.6) for CGI-S. Mean duration of treatment was approximately 8 weeks, producing a response rate of 81.8% and a remission rate of 27.3%. Only one patient was unable to tolerate the combination although nearly half (10) had significant side-effects during treatment. CONCLUSIONS This study demonstrates relatively high response and remission rates that are encouraging and contribute to the efficacy database for this antidepressant combination. Further studies using randomized controlled designs are needed.