Bone is sensitive to the removal of mechanical loading and the severity of unloading-induced bone loss may be influenced by an individual's genotype, gender, and the specific anatomical region. Whether these factors influence bone's mechanosensitivity directly or indirectly through differences in phenotypic baseline bone morphology and cellular activity is unknown. Here, we examined whether indices of baseline bone morphology and cellular activity are associated with the gender- and site-specific susceptibility of bone to unloading. Adult mice (4 months old, BALB/cByJ x C3H/HeJ) were assigned to one of six groups: male and female baseline controls (n=20 each), age-matched controls (n=10 each), or disuse (n=11 males, n=12 females). All baseline controls were sacrificed (0 day) to establish baseline bone morphology with micro-computed tomography (n=10 each gender) or baseline cellular activities using histomorphometry and tartrate-resistant acid phosphatase staining (n=10 each gender). Age-matched control and disuse mice were sacrificed (21 days) to determine disuse-induced bone loss by micro-computed tomography. Following 21 days of unloading, trabecular bone loss in the distal femur and proximal tibia was, on average, 3-fold greater in the metaphyses than in the epiphyses and 2-fold greater in females than in males. Disuse-induced changes in cortical bone were 2-fold smaller than trabecular bone losses and were more apparent in females (5 of 6 regions) than in males (1 of 6 regions). Bone loss was inversely related to baseline bone volume fraction (R(2)=0.51 for females and 0.43 for males) and directly related to baseline bone surface to volume ratio (R(2)=0.69 for females and 0.60 for males). Additionally, trabecular bone loss was correlated with baseline mineral apposition rates and osteoclast surface to bone surface ratios (R(2)=0.86 and 0.46, respectively, genders combined). These data demonstrate that baseline bone morphology and cellular activity modulate bone loss and that, independent of gender, anatomical regions with low bone quantity, high surface-to-volume ratios, and high levels of osteoblastic and osteoclastic activity are particularly susceptible to disuse.