The irreversible steroidal aromatase inhibitor exemestane (EXE) is one of three third generation aromatase inhibitors currently prescribed for advanced breast cancer in postmenopausal women. Its principal mechanism of action is to reduce estrogen by inhibiting its synthesis. In addition to its efficacy against breast cancer, its effects on other organs are important, especially when given to women with good-prognosis breast cancer or potentially to healthy women at increased risk of developing breast cancer. The purpose of this study was to evaluate the effects of EXE on bone and lipid metabolism in ovariectomized (OVX) rats. Ten-month-old Sprague-Dawley female rats were sorted into intact controls, intact + EXE, OVX controls, and OVX + EXE groups, and treated by weekly intramuscular injection with vehicle or 100 mg/kg EXE for 16 weeks. The bone mineral density (BMD), mechanical testing, histomorphometry, bone resorption marker-serum pyridinoline (PYD), and bone formation marker-serum osteocalcin (OC) were used to determine the effects of treatment on bone. In addition, total serum cholesterol, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were determined. BMD of the lumbar spine and femur were 11% and 7%, respectively, higher in OVX animals given EXE than in OVX controls (all Ps<0.001). Significant increases in the bending strength and toughness of the femora as well as the compressive strength and elastic modulus of the vertebrae were observed in OVX rats given EXE (all Ps<0.02 vs. OVX controls). Trabecular bone volume (BV) was significantly higher in OVX rats treated with EXE than in OVX controls (P<0.0001). In OVX animals, EXE reduced the OVX-induced increase of serum PYD by 96% (P<0.0001), and the OVX-induced increase of serum OC was completely prevented by treatment with EXE. In OVX animals, EXE resulted in a 28% reduction of serum cholesterol (P<0.0001) and reduced LDL by 64% compared with OVX controls (P<0.0001). The positive results of EXE on bone and lipid metabolism in the OVX rat model merit further investigation of the effects of EXE in postmenopausal women.