Background To determine the efficacy and safety of quetiapine combined with lithium or divalproex for preventing mood events in patients with bipolar I disorder. In this pooled analysis of two similar long‐term studies (D1447C00126 [NCT00107731] and D1447C00127 [NCT00081380]), lithium and divalproex treatment groups were analyzed separately. Methods Patients received open‐label quetiapine (400–800 mg/d) plus lithium or divalproex to achieve ≥12 weeks of clinical stability before being randomized to double‐blind combination treatment with quetiapine (400–800 mg/d) or placebo plus lithium or divalproex for up to 104 weeks. The primary endpoint was time to first mood event postrandomization following open stabilization. Results Of 3,414 patients in the stabilization phase, 1,326 were randomized. There were no differences in the risk of recurrence of mood, mania, or depression between quetiapine plus lithium or quetiapine plus divalproex. Among patients co‐treated with placebo and lithium, the risk of recurrence of a mania event was significantly higher than among patients co‐treated with placebo and divalproex. In patients with an index episode of mania, placebo plus lithium was associated with a significantly higher risk of recurrence of a mania event than placebo plus divalproex. Safety data were generally consistent with recognized safety profiles. Conclusions In patients with bipolar I disorder previously stabilized on quetiapine and lithium or divalproex, maintenance therapy with quetiapine significantly increased the time to recurrence of a mood event (mania or depression) versus placebo, regardless of whether it was combined with lithium or divalproex.