Estrogen replacement is a potent therapy for postmenopausal osteoporosis. However, its carcinogenic effects on breasts and the uterus limit its utilization. Raloxifene has estrogen-like effects on bones without the carcinogenic symptoms on breast or uterine tissue. Their individual effects are well characterized, but the results of their interaction remains elusive. In this work, we investigate the consequences of a combined raloxifene/estrogen therapy on bone and uterus with experimental osteoporosis. 40 Wistar rats began treatment 3 months post-ovariectomy. Estrogen and raloxifene were administered 0.03 mg/kg/day and 1.5 mg/kg/day separately and together for 5 times per week for 12 weeks. Biomechanical tests and bone mineral density measurements, histology of uterus, and blood markers were analyzed. The co-administration group had higher toughness and ultimate strength than the ovariectomized controls (P<0.01). E+R had better biomechanical properties than the single treatments; yet the differences were not significant. Uterus histology signified high degeneration in the estrogen group. The raloxifene group had less degeneration but higher vascularization. Less immune reaction and vascularization were observed in the group with combined dosage than in those with individual treatments. Hence, the uterus of the combined treatment had fewer side effects than the ones that were individually treated. Mutual antagonization might be possible between raloxifene and estrogen, and that might have caused a decrease in the adverse effects. Overall, combined therapy might be useful to minimize the individual side effects of raloxifene and estrogen on the uterus and still provide bone strength and toughness. (C) 2009 Elsevier B.V. All rights reserved.