Over the past few years, a number of studies have suggested that the treatment of major depressive disorder (MDD) with anti-depressants enhancing both noradrenergic as well as serotonergic neurotransmission may result in higher response or remission rates than treatment with anti-depressants selectively enhancing serotonergic neurotransmission. The objective of this paper was to compare response rates among patients with MDD treated with either mirtazapine, an anti-depressant thought to simultaneously enhance both noradrenergic and serotonergic neurotransmission, or selective serotonin reuptake inhibitors (SSRIs). Medline/Pubmed were searched. No year of publication limits were used. Double-blind, randomized clinical trials comparing mirtazapine with an SSRI for the treatment of MDD. Data were extracted with the use of a pre-coded form. Analyses were performed comparing response rates between the two anti-depressant agents. Data from 10 reports involving a total of 1904 outpatients with MDD were identified and combined using a random-effects model. Patients randomized to treatment with mirtazapine were as likely to experience clinical response as patients randomized to treatment with an SSRI (RR = 1.07; 95% CI: 0.96-1.2, P = 0.181). Simply pooling response rates between the two agents revealed a 67.1% response rate for mirtazapine and a 62.1% response rate for the SSRIs. There was no difference in overall discontinuation rates (RR = 1.1; 95% CI: 0.7-1.5; P = 0.550), discontinuation rates due to adverse events (RR = 0.9; 95% CI: 0.6-1.2; P = 0.497), or discontinuation rates due to lack of efficacy (RR = 0.9; 95% CI: 0.4-2.0; P = 0.871) between the two groups. Fewer mirtazapine-treated patients complained of insomnia (RR = 0.5; 95% CI: 0.3-0.9; P = 0.017), nausea (RR = 0.3; 95% CI: 0.3-0.5; P < 0.0001), whereas fewer SSRI-treated patients complained of fatigue (RR = 1.5; 95% CI: 1.1-2.4; P = 0.028), excessive sleepiness (RR = 1.3; 95% CI: 1.1-1.7; P = 0.020), weight-gain (RR = 3.8; 95% CI: 2.3-6.4; P < 0.0001) or dry mouth (RR = 1.8; 95% CI: 1.3-2.4; P < 0.0001) during the course of treatment. These results suggest that mirtazapine and the SSRIs differ with respect to their side-effect profile but not their overall efficacy in the treatment of MDD.