Background: There has been growing evidence supporting the use of atypical antipsychotic drugs as adjunctive treatments in patients with major depression who fail to respond adequately to antidepressants. Objective: To review the efficacy and safety data for one such combination, fluoxetine (FLX) + olanzapine (OLZ) in treatment-resistant depression (TRD). Methods: We reviewed published randomized, controlled acute-phase studies, as well as available long-term clinical studies. Results/conclusions: In each acute-phase study (n = 5), FLX/OLZ group experienced rapid antidepressant effects and, in two of these studies, resulted in significantly greater improvement at study end point compared with antidepressant monotherapy. These effects were strongest when TRD was defined as having failed at least two antidepressant trials during the current depressive episode. FLX + OLZ was generally well tolerated; however, increases in body weight and prolactin levels with FLX + OLZ were greater than that of antidepressant monotherapy groups and were similar to OLZ monotherapy. However, changes in random total cholesterol were also greatest for FLX + OLZ and were greater in magnitude than that of OLZ or FLX monotherapy. Long-term effectiveness/safety data are sparse, and comparison trials and sequential treatment studies involving FLX + OLZ and other antidepressant-atypical antipsychotic combinations are lacking. Thus, the exact place of FLX + OLZ among other available options for TRD is difficult to determine. © 2009 Informa UK Ltd. All rights reserved.