Objective Currently, there is a paucity of treatment options with limited efficacy for bipolar depression. The monoamine oxidase inhibitor tranylcypromine might be an effective form of treatment. The current systematic review reassesses the efficacy and safety of tranylcypromine in bipolar depression. Methods For this systematic review comparing tranylcypromine with placebo or active comparators in bipolar depression, relevant randomized controlled trials were identified from systematic searches of PubMed, EMBASE, and Cochrane library databases. A manual search of the references of the included studies was also performed. Results Four studies with a total of 145 participants were identified. Response rates were higher in patients treated with tranylcypromine (60.0%-80.7%; overall response rate, 73.7%) compared with placebo, imipramine, and lamotrigine (the latter as add-on to a mood stabilizer) (12.9%-47.6%; overall response rate, 27.5%). The overall switch rate was 6.3% for patients treated with tranylcypromine and 18.4% for patients in the control group. Conclusions This systematic review provides evidence for the efficacy and safety of tranylcypromine treatment in bipolar depression. Additional research is required to establish the efficacy of tranylcypromine as add-on to a mood stabilizer.