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Optically derived tissue properties across a range of breast densities and the effects of breast compression on estimates of hemoglobin, oxygen metabolism, and water and lipid concentrations were obtained from a coregistered imaging system that integrates near-infrared spectral tomography (NIRST) with digital breast tomosynthesis (DBT). Image data were analyzed from 27 women who underwent four IRB approved NIRST/DBT exams that included fully and mildly compressed breast acquisitions in two projections—craniocaudal (CC) and mediolateral-oblique (MLO)—and generated four data sets per patient (full and moderate compression in CC and MLO views). Breast density was correlated with HbT (r = 0.64, p = 0.001), water (r = 0.62, p = 0.003), and lipid concentrations (r = −0.74, p < 0.001), but not oxygen saturation. CC and MLO views were correlated for individual subjects and demonstrated no statistically significant differences in grouped analysis. Comparison of compressed and uncompressed imaging demonstrated a significant decrease in oxygen saturation under compression (58% versus 50%, p = 0.04). Mammographic breast density categorization was correlated with measured optically derived properties. [ABSTRACT FROM AUTHOR]