Multiple genes are involved in periodontal tissue remodeling in orthodontic tooth movement (OTM). Studies have attempted to establish the precise mechanism of remodeling during OTM. This study investigated the mechanism of action and functional roles of secretory leukocyte peptidase inhibitor (SLPI), a molecule enhancing tissue repair during OTM. The upper first molars of rats were moved mesially by applying a Ni-Ti coil spring on the upper incisors as an anchor. Primary cultures were prepared from human periodontal ligament (HPDL) cells and subjected to tension and compression forces. In vivo: The SLPI level increased at 1d, 2d, and 6d after OTM by real time-PCR and Western blot. Immunoreactivity against SLPI was mainly found in the PDL and enhanced in the tension and compression side. In vitro: SLPI worked by acting on MAPK pathways including ERK and p38. SLPI mRNA was upregulated by tension or compression. SLPI siRNA treatment induced upregulation of IL-6 and IL-8 in HPDL cells during the tension applications. However, SLPI siRNA treatment induced the downregulation of IL-8 during compression application. These results suggest that SLPI in the PDL may be involved in inflammation control in OTM.