IGF-I stimulates osteoblast proliferation, bone formation and increases bone volume in normal weight bearing animals. During skeletal unloading or loss of weight bearing bone becomes unresponsive to the anabolic effects of IGF-I. To determine whether skeletal reloading after a period of unloading increases bone responsiveness to IGF-I we examined bone structure and formation in response to IGF-I under different loading conditions. Twelve week old rats were divided into six groups; loaded (4 wks), unloaded (4 wks) and unloaded/reloaded (2/2 wks), and treated with IGF-I (2.5 mg/kg/d) or vehicle during the final two weeks. Cortical bone formation rate (BFR), cancellous bone volume and architecture in the secondary spongiosa (tibia and vertebrae), and total volume and calcified volume in the primary spongiosa (tibia) were assessed. Periosteal BFR decreased during unloading, remained low during reloading in the vehicle treated group but was dramatically increased in IGF-I treated animals. Cancellous bone volume decreased with unloading and increased with reloading but the effect was exaggerated in the tibia of IGF-I treated animals. Total and calcified volumes in the primary spongiosa decreased during unloading in the vehicle treated animals. IGF-I treatment prevented the loss in volume. These data show that reloading after a period of skeletal unloading increases bone responsiveness to IGF-I, and suggest that IGF-I may be of therapeutic use in patients who have lost bone as a consequence of prolonged skeletal disuse.