Given the high lifetime prevalence rates of bipolar disorder and comorbid substance use disorders (SUDs), the aim of the study was to examine the effect of a remitted SUD on the future course of bipolar I disorder in patients taking part in a clinical trial. Patients with bipolar I disorder were enrolled in a larger study examining the effects of pharmacotherapy plus family interventions. These patients were recruited during an acute mood episode and their mood symptoms and substance abuse were assessed longitudinally for up to 28 months. Patients with a remitted SUD showed a poorer acute treatment response, a longer time to remission of their acute mood episode, and a greater percentage of time with subthreshold but clinically significant depression and manic symptoms over follow-up compared to those without this comorbidity pattern. Subsequent substance abuse during follow-up could not fully account for the poorer course of illness. As remitted SUDs appear to negatively predict treatment outcome, current findings have implications for both clinical trials of bipolar patients as well as clinical practice.