Many patients with chronic skin disease develop hemostatic abnormalities. The blood coagulation factor XII is a multifunctional protease, which is involved in thrombosis, fibrinolysis, and inflammatory processes. The aim of this investigation was to assess the autoactivation of FXII that leads to the generation of FXII fragments and their subsequent cell penetration compared to UM8190, a lipophilic selective prolyl carboxypeptidase inhibitor compound. Terahertz scanning reflectometry (TSR) and terahertz spectrometry (TS) were used to study the surface-mediated FXII activation, as well as penetration of the FXII and UM8190, their retardant property, diffusion kinetics and fragmentation profiles into human stratum corneum (SC). From the diffusion kinetics and profiling experiments it was found that FXII does not penetrate the SC but remains mostly on the surface. Compound UM8190 indicates penetration into the SC, as indicated by the increased reflected intensity of T-ray. The terahertz spectral analysis via absorbance spectra indicates that at a low frequency of 0.56 THz a prominent peak occurs due to water or moisture for the SC alone. This peak, however, exhibits a shift for post-diffusion samples of both FXII saturated SC and UM8190-saturated SC. This is indicative of adhesion of these proteins onto the SC. Though this process corroborates the binding of FXII to the cell membrane surface as reported in the in vitro findings, it does not appear to be activated and degraded. It was also found that there are a number of absorbance peaks characteristic for each molecule and these peaks are uniquely shifted relative to each other when compared with the SC alone. Thus, these absorbance peaks may be utilized for assigning identifying features of the protein and peptides in this present study. Further investigation will be conducted for assigning the absorbance peaks to the specific proteins and their resonances.