The purpose of this study was to investigate the effect of antidepressant treatment on hippocampal volumes in patients with major depression. For 38 female outpatients, the total time each had been in a depressive episode was divided into days during which the patient was receiving antidepressant medication and days during which no antidepressant treatment was received. Hippocampal gray matter volumes were determined by high resolution magnetic resonance imaging and unbiased stereological measurement. Longer durations during which depressive episodes went untreated with antidepressant medication were associated with reductions in hippocampal volume. There was no significant relationship between hippocampal volume loss and time depressed while taking antidepressant medication or with lifetime exposure to antidepressants. Antidepressants may have a neuroprotective effect during depression.