Five independent studies show that polarity sequence is associated with prognosis in bipolar I disorder. Episodes in which major depression precedes mania (DMI) lead to higher morbidity than biphasic episodes which begin with mania (MDI). However, little is known about the prognostic significance of polarity sequence for long-term outcome. This study examined polarity sequence across multiple episodes among 165 bipolar I patients followed prospectively for up to 15 years as part of the NIMH Collaborative Study of Depression. Episodes beginning with major depression were significantly longer than those beginning with mania for the first three prospectively observed episodes when pooling all episode types-monophasic, biphasic, and polyphasic. Furthermore, affective polarity at onset for the first prospectively observed episode was associated with polarity at onset for the remaining three episodes. Patients whose first prospectively observed episode began with depression had higher overall morbidity during the entire follow-up period.