OBJECTIVES: The goal of this study was to evaluate the efficacy and safety of armodafinil as an adjunctive therapy for major depression associated with bipolar I disorder. METHODS: Patients 18-65 years of age with bipolar I disorder currently experiencing a major depressive episode while taking 1 or 2 mood stabilizer(s) and/or second-generation antipsychotics were randomized. The primary outcome was the mean change from baseline to week 8 in the 30-item Inventory of Depressive Symptomatology–Clinician-rated (IDS-C30) total score. RESULTS: 433 patients were randomized (n=199 placebo, n=201 armodafinil 150 mg, n=33 armodafinil 200 mg). Randomization to the 200 mg armodafinil group was discontinued early; only safety results from this group are presented. For the armodafinil 150 mg group compared with placebo, there was a significantly greater decrease in LS mean (SEM) IDS-C30 total score (−21.7 [1.11] vs −17.9 [1.10]; P=0.0097) at week 8 and the percentage of IDS-C30 responders (≥50% decrease from baseline) was significantly greater at week 8 (55% vs 39%; P=0.0084) and final visit (46% vs 34%; P=0.0147). The most common AEs were headache (9.6% vs 10.1%), diarrhea (8.6% vs 6.5%), and nausea (5.6% vs 4.5%) for the armodafinil 150 mg and placebo groups, respectively, and headache (21.9%), insomnia (12.5%), and nausea (9.4%) for the armodafinil 200 mg group. At final visit, 5% (9/183) of patients in the placebo group, 2% (3/186) of the 150 mg group, and 4% (1/28) of the 200 mg group had potentially clinically significant (≥7%) weight gain from baseline. CONCLUSIONS: Armodafinil 150 mg significantly improved depressive symptoms compared with placebo in patients with a major depressive episode associated with bipolar I disorder when given as adjunctive treatment to mood stabilizers. Safety data indicate that adjunctive armodafinil 150 mg was generally well tolerated.