Abstract Background: A previous pilot study of open-label mirtazapine augmentation conducted by the authors in 20 depressed patients yielded a 55% response rate at week 4. A double-blind controlled trial was undertaken to further elucidate the efficacy of this intervention. Methods: 26 adult outpatients with persistent major depression despite adequate antidepressant monotherapy were randomized to receive 4 weeks of mirtazapine or placebo augmentation. Mirtazapine was begun at 15 mg at bedtime, with possible titration to 30 mg at bedtime per physician’s discretion after week 1. Results: Categorical positive response rate at end point was 64% for active drug and 20% for placebo. Remission rates were 45.4% and 13.3% for active drug and placebo groups, respectively, Mirtazapine demonstrated statistically significant superiority to placebo on most major outcome measures, and was associated with improvement in overall functioning and quality of life. There were no significant group differences with regard to emergent side effects, weight change, or serum concentrations of primary antidepressants. Conclusions: Mirtazapine appears safe and effective for short-term antidepressant augmentation.