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Background: Bipolar affective disorder (BPAD) is an illness with high morbidity and mortality. Lithium and other anticonvulsant drugs are the main treatments for BPAD, despite little being known about their mechanisms of action. Recent attempts to elucidate the biochemical actions of these drugs have focused on the protein kinase C (PKC) pathways. Another PKC inhibitor hypothesized to be effective in the treatment of mania is tamoxifen, a synthetic nonsteroidal antiestrogen. The aim of the current study was to test and compare the effectiveness of two adjunctive antiestrogen agents (tamoxifen or progesterone) in the treatment of acute mania. Methods: A 28-day, three-arm (40 mg/day oral tamoxifen or 20 mg/day oral progesterone or oral placebo), double-blind, placebo-controlled, adjunctive study of 34 women with mania was conducted. All patients also received a mood stabilizer as the baseline treatment. Manic symptoms and psychopathology were measured weekly using the CARS-M and Positive and Negative Syndrome Scale rating scales together with estrogen, progesterone and gonadotropin levels. Cognitive functioning (RBANS) was assessed in a subsample of fi ve participants at baseline and repeated on day 28. Results: Results indicated a decline in the symptoms of mania and psychopathology in the tamoxifen group, and to a lesser extent in the progesterone and control groups. The tamoxifen group also had signifi cant changes in estrogen levels, as well as correlations between estrogen and mania ratings. Conclusion: The results suggest that tamoxifen may be a useful adjunct in the treatment of acute manic symptoms in women with BPAD.