Purpose: A high-resolution cone-beam CT (CBCT) system for extremity imaging has been developed using a custom complementary metal–oxide–semiconductor (CMOS) x-ray detector. The system has spatial resolution capability beyond that of recently introduced clinical orthopedic CBCT. We evaluate performance of this new scanner in quantifying trabecular microstructure in subchondral bone of the knee. Methods: The high-resolution scanner uses the same mechanical platform as the commercially available Carestream OnSight 3D extremity CBCT, but replaces the conventional amorphous silicon flat-panel detector (a-Si:H FPD with 0.137 mm pixels and a ~0.7 mm thick scintillator) with a Dalsa Xineos3030 CMOS detector (0.1 mm pixels and a custom 0.4 mm scintillator). The CMOS system demonstrates ~40% improved spatial resolution (FWHM of a ~0.1 mm tungsten wire) and ~4x faster scan time than FPD-based extremity CBCT (FPD-CBCT). To investigate potential benefits of this enhanced spatial resolution in quantitative assessment of bone microstructure, 26 trabecular core samples were obtained from four cadaveric tibias and imaged using FPD-CBCT (75 μm voxels), CMOS-CBCT (75 μm voxels), and reference micro-CT (μCT, 15 μm voxels). CBCT bone segmentations were obtained using local Bernsen’s thresholding combined with global histogram-based pre-thresholding; μCT segmentation involved Otsu’s method. Measurements of trabecular thickness (Tb.Th), spacing (Tb.Sp), number (Tb.N) and bone volume (BV/TV) were performed in registered regions of interest in the segmented CBCT and μCT reconstructions. Results: CMOS-CBCT achieved noticeably improved delineation of trabecular detail compared to FPD-CBCT. Correlations with reference μCT for metrics of bone microstructure were better for CMOS-CBCT than FPD-CBCT, in particular for Tb.Th (increase in Pearson correlation from 0.84 with FPD-CBCT to 0.96 with CMOS-CBCT) and Tb.Sp (increase from 0.80 to 0.85). This improved quantitative performance of CMOS-CBCT is accompanied by a reduction in scan time, from ~60 sec for a clinical high resolution protocol on FPD-CBCT to ~17 sec for CMOS-CBCT. Conclusion: The CMOS-based extremity CBCT prototype achieves improved performance in quantification of bone microstructure, while retaining other diagnostic capabilities of its FPD-based precursor, including weight-bearing imaging. The new system offers a promising platform for quantitative imaging of skeletal health in osteoporosis and osteoarthritis.