The efficacy of estrogen replacement therapy (ERT) for mood disturbances associated with menopause has yet to be firmly established. The objective of this study was to investigate the efficacy of ERT for improving mood and anxiety of non-depressive postmenopausal women. This double-blind, randomized, placebo-controlled study involved two treatment groups: one receiving conjugated equine estrogens (CEEs; 0.625 mg/day) and the other placebo, for six cycles of 28 days each. Subjects were hysterectomized, healthy, non-depressive (according to Schedule for Affective Disorders and Schizophrenia, Life Time Version [SADS-L]) women. Depressive and anxiety symptoms were assessed with the Beck Depression Inventory (BDI), and the Hamilton Anxiety Scale (HAMA), respectively. The Profile of Mood States (POMS) and other scales were used to characterize symptoms. In both groups, BDI scores were significantly lower at cycles 1, 2, 3, and 6, compared with baseline assessments (p<0.01). Anxiety scores for both groups significantly improved from cycle 3 to study endpoint. The only significant difference favoring the active group occurred at cycle 1. POMS scores were significantly improved at the end of cycles 1, 2, 3 and 6 among treated subjects and at the end of cycles 2, 3, and 6 among placebo subjects. ERT is not associated with improvements in mood or anxiety symptoms in non-depressive, hysterectomized, postmenopausal women.