Background: Many women with no past psychiatric history experience severe mood symptoms for the first time in their life during the menopausal transition, with debilitating long-term consequences. Women with a history of depression can experience a relapse or worsening of symptoms during the menopause transition. Traditional antidepressants, SSRIs or SNRIs, are commonly prescribed as the first line response. However, such treatment has shown only small improvements with side effects. Hormone therapies directly targeting the perimenopausal fluctuations in reproductive hormonal systems such as tibolone, have significant potential to treat perimenopausal depression. Our study investigated the use of adjunctive tibolone, selective tissue estrogenic activity regulator, to treat de-novo or relapsing depression occurring during the menopause transition period. Methods: Women who were going through the menopause transition with depressive symptoms were invited to participate in a double-blind, 12 week randomized control trial with two arms: tibolone (2.5 mg oral/day) or oral placebo (NCT01470092). Forty-four women met inclusion/exclusion criteria; 22 were randomized to tibolone and 22 were randomized to oral placebo. Symptoms were measured with the ‘Montgomery- Asberg depression rating scale’ (MADRS) as the primary outcome measure. Latent growth curve analysis was used to assess the MADRS scores change over time. Results: Participants in the tibolone group demonstrated a significant improvement in depression scores, as compared to the placebo group, without any significant side effects. Limitations: This trial only monitored tibolone's effects over 12 weeks. Future research should be conducted over an extended timeframe and explore whether the benefits of tibolone extend to other symptoms of perimenopausal depression. Conclusions: The use of hormone therapies such as tibolone provide exciting innovations for the treatment of depression during the menopause transition.