Introduction: The skin is considered the first barrier against the penetration of laser light into the body, which causes limitations in imaging or treatment with laser light. The constituents of the skin, which are mainly proteins, lipids, interstitial water, and blood vessels, cause severe light scattering and limit the penetration of light into the deep tissues. This limitation causes the lack of access to structural information and tissue constituents by light and a decrease in the resolution of optical imaging. In this study, using semi-natural HPMC polymer, sorbitol, coconut oil and Tween 20 (called CSC1 and CSC2 for short), the optical parameters of the skin tissue sample were determined by the diffuse reflection spectrum (DRS) method. Research method: DRS was used to obtain the reflection and transmission spectra of the tissue. Then, by using the obtained values and placing them in the Kramers-Kronig relationship, the refractive index can be obtained before and after applying optical clearing agent. Also, other optical parameters such as absorption coefficient, total attenuation coefficient and diffusion coefficient have been calculated from reflection and transmission spectra. Findings: The effect of using optical clearing agent (CSC1, CSC2) on variation of optical properties of sample (refractive index, absorption coefficient, and diffusion coefficient) are measured. Conclusion: The results show that the semi-natural HPMC polymer, which played a role in maintaining the structure of the solution, was effective. Therefore, it can be concluded that the CSC2 could better clear the sample, and it improves the optical depth.