To determine the efficacy and tolerability of olanzapine/fluoxetine combination (OFC) compared with lamotrigine (Lam) for long-term treatment of bipolar I depression, this 25-wk, randomized, double-blind study compared OFC (6/25, 6/50, 12/25, or 12/50 mg/d, n=205) with Lam titrated to 200 mg/d (n=205) in patients with bipolar I disorder, depressed. A protocol-specified analysis of 7-wk outcomes was previously reported. Outcome measures included Clinical Global Impressions – Severity of Illness (CGI-S) (primary), Montgomery–Asberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS) scores. OFC-treated patients had significantly greater improvement than Lam-treated patients over 25 wk on CGI-S (p=0.008), MADRS (p=0.005), and YMRS (p<0.001) scores, and from baseline across visits from week 5 (titration complete) to the end of the study on CGI-S (p=0.043), MADRS (p=0.017), and YMRS (p=0.001) scores. Of patients in remission after the 7-wk acute phase, there was no significant difference between treatment groups in the incidence of relapse (MADRS >15, p=0.528). Rate of treatment-emergent mania was not significantly different by treatment (p=0.401). OFC-treated patients had more frequent (p<0.05) somnolence, increased appetite, dry mouth, sedation, weight gain, and tremor; Lam-treated patients had more frequent insomnia. There was a significant difference in incidence of treatment-emergent cholesterol ⩾240 (p<0.001) and in weight gain of ⩾7% (p<0.001) in favour of the Lam group. Patients with bipolar I depression had significantly greater symptom improvement over 25 wk on OFC compared with Lam. There was no treatment difference in incidence of relapse. OFC-treated patients had more treatment-emergent adverse events and greater incidence of weight gain and hypercholesterolaemia.