Low circulating IGF-I is associated with increased fracture risk. Conditional depletion of IGF-I produced in osteoblasts or osteocytes inhibits the bone anabolic effect of mechanical loading. Here, we determined the role of endocrine IGF-I for the osteogenic response to mechanical loading in young adult and old female mice with adult, liver-specific IGF-I inactivation (LI-IGF-I^-/- mice, serum IGF-I reduced by 70%) and control mice. The right tibia was subjected to short periods of axial cyclic compressive loading, 3 times a week for 2 weeks, and measurements were performed using micro-computed tomography (µCT) and mechanical testing by three-point bending. In the non-loaded left tibia, the LI-IGF-I^-/- mice had lower cortical bone area and increased cortical porosity, resulting in reduced bone mechanical strength compared to the controls. Mechanical loading induced a similar response in LI-IGF-I^-/- and control mice in terms of cortical bone area and trabecular bone volume fraction (BV/TV). In fact, mechanical loading produced a more marked increase in cortical bone mechanical strength, associated with a less marked increase in cortical porosity, in the LI-IGF-I^-/- mice compared to the control mice. In conclusion, liver-derived IGF-I regulates cortical bone mass, cortical porosity, and mechanical strength under normal (non-loaded) conditions. However, despite an approximately 70% reduction in circulating IGF-I, the osteogenic response to mechanical loading was not attenuated in the LI-IGF-I^-/- mice.