The objective of this report is to compare antidepressant response rates and tolerability in younger and older women. One hundred fifteen female outpatients who met DSM-IV criteria for major depressive disorder were evaluated before and after 8 weeks of treatment with a selective serotonin reuptake inhibitor, nefazodone, or venlafaxine. The sample was divided into younger and older groups based on age to approximate premenopausal and postmenopausal status. Eighty-six age-matched male outpatients formed the comparison group. Younger women compared with older women had significantly lower Hamilton Rating Scale for Depression scores after 8 weeks of antidepressant treatment and achieved significant higher rates of remission. There were no differences in overall drug tolerability. This pattern was not replicated in the male patients. Younger women with depression are more responsive to serotonergic antidepressants. This may relate to changes in menstrual status. Limitations of the study and implications for the role of female sex hormones are discussed. Future investigations should include measurement of reproductive hormone levels.