Objective: Some experimental and observational data suggest a role of estrogen in depression. Raloxifene is a selective estrogen receptor modulator (SERM) approved for the prevention and treatment of postmenopausal osteoporosis. Its influence on mood in postmenopausal women has not been fully established. Thus, we investigated the effect of raloxifene on mood. Methods: In a randomized double-blind osteoporosis prevention study, the action of raloxifene on mood was assessed in a subgroup of non-depressed postmenopausal women (mean age: 58.9 years) receiving raloxifene 60 mg/day (n=18) or placebo (n=18). The Hamilton Depression Rating Scale (HDRS) was applied to evaluate mood 3 and 12 months following treatment. Results: Baseline HDRS scores were not different among treatment groups. Overall scores decreased from baseline at 3 and 12 months in the raloxifene group (P≤0.006), but not in the placebo group. Depression and anxiety indexes decreased in the raloxifene group at 3 and 12 months (P≤0.04); only anxiety index at 12 months decreased in the placebo group (P=0.045). Conclusions: These preliminary results suggest that raloxifene does not negatively influence mood in non-depressed, younger postmenopausal women. Larger, long-term studies are required to evaluate a possible mood improvement effect of raloxifene.