Objectives: Matrix metalloproteinases (MMPs) and cysteine cathepsins (CC) are partly responsible for the degradation of exposed dentin collagen in hybrid layer. This study evaluated the effect of specific inhibitors on the MMP-mediated or CC-mediated degradation of dentinal collagen. Methods: Dentin beams (1x2x6mm) were completely demineralised in 10% phosphoric acid (24h). After baseline measurements of dry mass, the beams were divided into 7 groups (n=10/group). The groups were incubated in 1mL simulated body fluid (SBF) with 1) 500 µM E-64 at pH 6; 2) 500 µM E-64 at pH 7.2; 3) 50 µM Galardin at pH 6; 4) 50 µM Galardin at pH 7.2 ; 5) 500 µM E-64 and 50 µM Galardin, pH 7.2; 6) SBF, pH 6; 7) SBF, pH 7.2 for 6 hrs, 18 hrs, 3 days and 1 week at 37°C shaking bath. After each time point, beams were re-weighed to determine dry mass loss and aliquots of incubation media were analyzed for pyridinoline-crosslink-containing degradation fragment of the C-terminal-telopeptide of type I collagen (ICTP) as a determinant for MMP-mediated degradation and deoxypyridinoline-containing degradation fragment of C-terminal telopeptide (CTX) as a determinant for CC-mediated degradation using ELISA kits. The data were analyzed using ANOVA, α=0.05. Results: The ICTP release was 10-fold higher compared to the CTX release. The CTX release at 6 hrs were significantly higher compared to all other time points (p<0.05). The rate of dry mass loss changed significantly between groups at different time points p<0.05. Groups containing Galardin at pH 7.2 showed significantly lower mass loss (12%), compared to control at pH 7.2 (19%) p<0.05. Conclusions: The results of this study indicate that overall CC-mediated collagen degradation is lower compared to MMP-mediated collagen degradation. Early CC activity may further activate MMPs leading to an increased MMP-mediated degradation.