Sclerostin antibody (Scl-Ab) is a novel bone-forming agent that is currently undergoing preclinical and clinical testing. Scl-Ab treatment is known to dramatically increase bone mass, but little is known about the quality of the bone formed during treatment. In the current study, global mineralization of bone matrix in rats and nonhuman primates treated with vehicle or Scl-Ab was assayed by backscattered scanning electron microscopy (bSEM) to quantify the bone mineral density distribution (BMDD). Additionally, fluorochrome labeling allowed tissue age–specific measurements to be made in the primate model with Fourier-transform infrared microspectroscopy to determine the kinetics of mineralization, carbonate substitution, crystallinity, and collagen cross-linking. Despite up to 54% increases in the bone volume after Scl-Ab treatment, the mean global mineralization of trabecular and cortical bone was unaffected in both animal models investigated. However, there were two subtle changes in the BMDD after Scl-Ab treatment in the primate trabecular bone, including an increase in the number of pixels with a low mineralization value (Z5) and a decrease in the standard deviation of the distribution. Tissue age–specific measurements in the primate model showed that Scl-Ab treatment did not affect the mineral-to-matrix ratio, crystallinity, or collagen cross-linking in the endocortical, intracortical, or trabecular compartments. Scl-Ab treatment was associated with a nonsignificant trend toward accelerated mineralization intracortically and a nearly 10% increase in carbonate substitution for tissue older than 2 weeks in the trabecular compartment (p < 0.001). These findings suggest that Scl-Ab treatment does not negatively impact bone matrix quality. © 2014 American Society for Bone and Mineral Research.