Objective: To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants. Method: Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study. Results: Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02). Conclusion: There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded. © 2007 The Author.