In this paper, we demonstrate the use of a relatively low system cost, high measurement efficiency diffuse reflectance spectroscopy (DRS) technique to characterize the optical properties of keloid and normal skin in vivo. Different from the multi-photon microscopy that provides structural information of tissues, DRS is useful for obtaining the macroscopic information, such as scattering property, collagen concentration, and hemoglobin concentration, of tissue samples. DRS has been employed to study the optical properties of various types of biological tissue, for example, brain, breast, and skin.14–16 The general measurement configuration of this technique involves the injection of visible to near-infrared light into the tissue under investigation as well as the collection of the diffuse reflectance from the tissue using a detector placed on the same side with the light source. A photon transport model is usually needed to recover the absorption and scattering properties of samples from the measured diffuse reflectance. Moreover, the absorption spectra derived from the DRS measurements can be further translated into the concentrations of tissue chromophores: hemoglobin, melanin, water, and lipid, for instance. The average interrogation depth of DRS is proportional to the separation between the source and the detector at a given source wavelength.17 The interrogation depth of DRS reduces dramatically as the source wavelength approaches visible and infrared regions due to the strong absorption features of hemoglobin and water, respectively. In general, DRS measurements employing source-detector separations larger than 10 mm can work with a simple, efficient “standard diffusion model” in the near infrared region, where tissue absorption and scattering are relatively low, to investigate the functional information, such as oxygen saturation and status of edema, of deep tissues such as breast and muscle.15,18 Lately, Nachabe et al. and Taroni et al. reported the use of DRS techniques to quantify the collagen content of breast tissues.19,20 They found that the collagen concentration of in vivo biological tissues can be reasonably derived, and it could be used as one of important factors for the breast tumor classification.