The authors investigated whether there were differences in cerebral and cerebellar gray and white matter volumes in depressed patients compared to controls, and whether this was associated with treatment response to fluoxetine. Brain magnetic resonance images were obtained from 38 unipolar depressed patients and 20 age, gender, and educationally matched comparison subjects. Patients were divided into groups of "responders" and "nonresponders" based on change in 17-item Hamilton Depression Rating Scale (HDRS) after an 8-week standardized trial of fluoxetine, 20 mg/day. There were no group mean differences in cerebral or cerebellar tissue volumes between patients and controls, or responders and nonresponders. For nonresponders to fluoxetine treatment, cerebral and cerebellar gray matter volume, and total cerebellar tissue volume decreased as baseline HDRS increased. The results suggest an association between gray matter volume and severity of illness in nonresponders to fluoxetine treatment.