The highly scattering nature of human tissue limits light penetration depth in the near infrared range, which prevents the deeper microstructures from imaging. In order to enhance the imaging depth for the current high resolution optical imaging techniques, the light scattering in tissue must be reduced. This paper demonstrates that the light scattering of tissue can be effectively reduced by the topical applications of the biocompatible chemical agents. In this study the propylene glycol and glucose solutions were chosen for the demonstrations through topical applications and intra-dermis injection, respectively. The experiments were performed in vitro and in vivo by the use of the optical coherence tomography system. The results clearly show that the OCT imaging depth and contrast are dramatically improved after the topical applications of propylene glycol solution. Such improvement was discussed on the basis of refractive index matching environment created by the chemical agents, which effectively reduces the light scattering of tissue. Rayleigh-Gans approximation of light scattering was also used to show theoretically how the increase of refractive index of background medium would have effect on the reduced scattering coefficient of tissue. The theoretical and experimental results were qualitatively consistent.© (2003) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.