Transillumination breast spectroscopy (TiBS) uses nonionizing optical radiation to gain information about breast tissue morphological and structural properties. TiBS spectra are obtained from 232 women and compared to mammographic density (MD) quantified using Cumulus. The ability of TiBS to estimate MD is assessed using partial least-squares (PLS) regression methods, which requires TiBS spectra as input and Cumulus MD as target data. Multiple PLS models are considered to determine the optimal processing technique(s) for the input and target data. For each model, the association between TiBS estimated MD and Cumulus MD is established using Spearman’s rank correlation and linear regression analysis. The model that best estimates MD has the fewest assumptions regarding target and spectral processing. The Spearman’s correlation coefficient between predicted MD and Cumulus MD for this model is 0.88, with a regression slope of 0.93 (95% CI 0.83–1.02) and an of 0.78. The approximation of individual MD was within 10% of Cumulus MD for the majority of women (80%), without stratification on age, body mass index (BMI), and menopausal status. TiBS provides an alternative to mammography assessed MD enabling frequent and earlier use of MD as a risk marker in preventive oncology.