In quest of the most simple and effective treatment for in vivo skin experiments, thiazone was used as an enhancer in our study. To compare with the pure polyethyleneglycol 400 (PEG400) solution, the mixed solution (thiazone in combination with) was applied on the stratum corneum partly removed skin and intact skin respectively. For visual observation, photographs of the local skins were taken by CCD; and then the light reflectance spectra of skin were monitored. The results showed that a mixed solution could make the skin without stratum corneum more transparent in 15 min, with the reflectance spectrum decreased significantly; while there’s no observable change in the intact skins. However, the pure PEG400 did not have optical clearing effects on any skins. In conclusion, the non-invasive drug delivery method, which is combined with physically abrading part of the stratum corneum and adding chemical enhancer-thiazone, can improve the effect of PEG400 in skin optical clearing quickly and effectively.