Estrogen (E) treatment has proven to be effective in preventing bone loss after menopause with, however, some undesirable side effects. Many of these side effects are related to the hormone's actions on reproductive tissues. Raloxifene is an organ-selective estrogen agonist that prevents acute cancellous osteopenia in ovariectomized (OVX'd) growing rats. The effects of raloxifene on adult rats with established bone loss are not known. We now compare the dose response effects of 4 months of treatment with raloxifene and estrogen in 8-month-old rats that had been OVX'd 2 months before treatment. OVX resulted in increased body weight, uterine atrophy and severe cancellous bone loss. Estrogen resulted in a dose-dependent increase in uterine weight in OVX'd rats whereas raloxifene did not promote uterine growth. Both treatments reduced body weight and serum cholesterol. Raloxifene and estrogen were each effective in stabilizing cancellous bone by preventing additional cancellous bone loss, but neither treatment replaced lost bone. These findings provide further evidence that raloxifene is a much more potent estrogen agonist on the skeleton and liver than on the uterus.