OBJECTIVE: Neuroimaging studies reveal abnormalities of regional cerebral blood flow (rCBF) in major depression. In this study the authors prospectively investigated rCBF and clinical response to venlafaxine, a novel antidepressant. METHOD: A trial of venlafaxine was performed with seven patients referred with ICD-10 major depression. At entry and 6-week follow-up, the Beck Depression Inventory and Hamilton Depression Rating Scale were administered and rCBF was measured by means of single photon emission computed tomography with [99mTc]hexamethylpropyleneamine oxime. Blood flow changes were explored with statistical parametric mapping. RESULTS: The subjects showed significant improvement after treatment. Statistical parametric mapping analysis revealed increased rCBF bilaterally in the thalamus and decreased rCBF in the left occipital lobe, right cerebellum, and temporal cortex bilaterally. CONCLUSIONS: These data confirm limbic cortical rCBF changes associated with effective antidepressant treatment.