We examined the effects of sertraline and of desipramine on patients with OCD and comorbid major depressive episodes at study entry. Sixteen patients, 9 receiving sertraline and 7 desipramine, received HMPAO SPECT scans while free of medication and after 12 weeks of treatment. Patients on sertraline showed significantly reduced regional cerebral blood flow (rCBF) in the right prefrontal and temporal regions. Patients on desipramine showed more diffuse rCBF reductions in frontal and temporal regions, more so in the left side. In a second analysis, patients who had a symptom reduction on the Yale-Brown Obsessive Compulsive Scale (YBOCS), irrespective of the type of medication, were retrospectively classified as 'responders' to treatment. Eleven patients were 'responders' and 5 'non-responders'. Before being medicated, responders differed from non-responders through higher rCBF in prefrontal regions, mostly on the left, and higher rCBF in the cingulate and basal ganglia bilaterally. After 12 weeks of treatment, responders showed a diffuse reduction of rCBF in prefrontal regions while non-responders showed only a few scattered low-frequency responses. Thus, higher prefrontal and subcortical activity was associated with better response to drug treatment. In addition, clinical change, but not the administration of medication as such, was associated with a decrease of prefrontal rCBF.