Studies of mood provocation in remitted patients with depression have enabled the description of specific brain changes relevant to depression relapse vulnerability. Because patients in these studies were also receiving maintenance pharmacotherapy, the ability to subtract out the drug effect from the changes observed is reduced. Our study addresses this concern. Changes in regional cerebral blood flow (rCBF) among 11 medication-free, remitted patients with unipolar depression relative to baseline state were assessed with [(15)O]H(2)O positron emission tomography (PET) following provocation of sadness. Participants showed decreased activation in prefrontal cortex similar to those reported for remitted, medicated patients undergoing mood challenge, as well as for acutely depressed patients who were medication free. Previously reported mediofrontal changes in remitted patients are unlikely to be a consequence of maintenance medication and more likely are evidence of relapse vulnerability.