The issue of whether long-term sodium warfarin therapy results in decreased bone density is controversial. To address this question, we randomized rats to once daily subcutaneous injections of either sodium warfarin (0.20 or 0.25 mg/kg) or saline for 28 days and monitored the effects on bone, both biomechanically and by histomorphometric analysis. In addition, the anticoagulant status of both saline- and warfarin-treated rats were monitored throughout the course of the experiment by measuring the prothrombin time, expressed as international normalized ratios (INRs). Rats treated with 0.25 mg/kg warfarin demonstrated INRs of approximately 2.6, while rats treated with either 0.20 mg/kg warfarin or saline were found to have INRs of 1.3 and 1.0, respectively. Biomechanical testing of the right femur of rats treated with 0.25 mg/kg warfarin demonstrated that warfarin caused an 8% reduction in bone strength as measured by maximum tolerated load. A similar reduction in the biomechanical parameters of energy to break (P<.0001) and force at break point (P<.005) was also observed. Histomorphometric analysis of the left femur of warfarin-treated rats revealed a 17% reduction in cancellous bone volume. This was accompanied by a 60% decrease in osteoblast surface, as well as an 80% reduction in osteoid surface. In contrast, warfarin treatment had the opposite effect on osteoclast surface, which was 35% higher following warfarin treatment. Based on these observations, we conclude that clinically relevant doses of warfarin decrease femoral bone strength and cancellous bone volume, both by decreasing the rate of bone formation and increasing the rate of bone resorption.