Abstract: Olanzapine is an effective drug for the long-term treatment of bipolar disorder but is associated with burdensome weight gain. Topiramate is a novel anticonvulsant that may induce weight loss in some patients. This is the first study to address the long-term efficacy and impact on weight of the combination of olanzapine and topiramate in bipolar patients. Twenty-six Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition bipolar spectrum patients received olanzapine plus topiramate cotherapy for treatment of their manic (n = 14), hypomanic (n = 6), depressive (n = 2), and mixed (n = 1) symptoms for 1 year. Three rapid cycling patients were also enrolled despite being euthymic. Efficacy was assessed with the Young Mania Rating Scale, the Hamilton Depression Rating Scale, and the Modified Clinical Global Impressions for Bipolar Disorder. Weight, body mass index, and side effects were collected at every visit. Thirteen (50%) patients completed the 1-year follow-up. By intent-to-treat, patients significantly improved from baseline in Young Mania Rating Scale scores (P < 0.0001), Hamilton Depression Rating Scale (P < 0.05), and Modified Clinical Global Impressions for Bipolar Disorder subscales (mania P < 0.0001, depression P < 0.05, overall P < 0.0001). Most patients gained weight during the first month of combined treatment (mean weight gain 0.7 ± 0.6 kg), but at the 12-month endpoint, the mean weight change was −0.5 ± 1.1 kg. The combination of olanzapine and topiramate was efficacious for the long-term treatment of bipolar patients and appeared to carry some benefits for controlling weight gain. Given the limitations of the open, uncontrolled design, further trials are warranted with this combination.