Recent studies suggest that inflammatory cell products may contribute to the evolution of particular cancers leading to new chemoprevention trials exploring the benefit of anti-inflammatory drugs such as aspirin and related products. As part of a prospective trial evaluating this anti-inflammatory strategy for oral cancer, we evaluated a non-invasive optical system to determine if we could use an indirect measure of oral inflammation, mucosal thickness, as a monitoring parameter to evaluate the effectiveness of anti-inflammatory drug therapy. Diffuse reflectance spectroscopy has the potential for probing near-surface structures, however, traditional methods for accounting for scattering of photons are generally invalid for typical epithelial thicknesses. Monte Carlo simulations have shown that, with proper scaling, a simple photon model may be used to predict photon behavior under these conditions. A differential measure, which is very sensitive to small changes, has been shown to have the potential to quantify epithelial thickness. A simple prototype device has been brought from desk, to bench and bedside in a rapid manner to fill a need for a non-invasive measure of oral inflammation. From the theory, a simple feature has been identified that corresponds to patient oral inflammation. Preliminary results from this work are presented and indicate that further development of the approach to enable quantification of epithelial thickness in vivo is warranted.