Depression is the predominant mood state in patients with bipolar I or II disorder over the course of illness. In spite of this, relatively few pharmacological treatments have been shown to be effective for treating depressive episodes associated with bipolar disorder in adults. Combination therapy with olanzapine and fluoxetine (OFC) is approved in the US for the treatment of acute depressive episodes in adults with bipolar I disorder. The short-term efficacy and safety of OFC for the treatment of bipolar depression are supported by results of four randomized, acute-phase studies. OFC has been associated with significantly greater depressive symptom improvement than placebo, and with higher rates of treatment response and remission than placebo and olanzapine monotherapy. OFC has also been shown to improve depressive symptoms to a greater degree than modestly dosed lamotrigine, with similar rates of positive treatment response and remission. Although OFC was generally well tolerated in each of the reviewed studies, clinically significant weight gain, adverse changes in glycemic and lipid profile, and prolactin elevation may complicate both short- and long-term treatment. OFC was not associated with significantly increased risk of treatment-emergent mania in any of the reviewed studies. The broader effectiveness of OFC for the treatment of bipolar depression across clinically relevant subtypes (eg, patients with bipolar II disorder and comorbid substance abuse) and over long-term follow-up are needed. Comparative effectiveness studies of OFC and other available agents are also needed in order to determine its place among other available options for treating acute bipolar depressive episodes. © the author(s), publisher and licensee Libertas Academica Ltd.