BACKGROUND: Even in remission, patients with bipolar disorder (BD) remain sensitive to external stressors that can trigger new episodes. Imitating such stressors by the controlled transient exposure to an emotional stimulus may help to identify brain regions modulating this sensitivity. METHODS: Transient sadness was induced in 9 euthymic and in 11 depressed subjects with BD. Regional blood flow (rCBF) changes were measured using (15)O-water positron emission tomography. RESULTS: Common changes in both groups were increased rCBF in anterior insula and cerebellum and decreased rCBF in dorsal-ventral-medial frontal cortex, posterior cingulate, inferior parietal, and temporal cortices. Decreases in dorsal ventral medial frontal cortices occurred in both groups, but subjects in remission showed a greater magnitude of change. Unique to remitted subjects with BD were rCBF increases in dorsal anterior cingulate and in premotor cortex. Lateral prefrontal rCBF decreases were unique to depressed subjects with BD. At baseline, remitted subjects showed a unique increase in dorsal anterior cingulate and orbitofrontal cortex. CONCLUSIONS: Common rCBF changes in remitted and depressed subjects identifies potential sites of disease vulnerability. Unique cingulate and orbitofrontal changes both at baseline and with induced sadness seen in the absence of prefrontal rCBF decreases may identify regional interactions important to the euthymic state in this population.