Metabolism by peptidases plays an important role in modulating the levels of biologically active neuropeptides. One of these neuropeptides, substance P (SP), a component of gingival crevicular fluid (GCF), may exponentiate the inflammatory process during orthodontic tooth movement. The aim of this study was to investigate the GCF levels of SP in patients using different bracket systems. Subjects were 10 patients (four males, six females; mean age, 25.1 ± 4.4 years) undergoing orthodontic movement (leveling) in the maxilla. Conventional brackets were placed on the left side, while the teeth on the right received self-ligating brackets. The teeth on the mandibular left side without any orthodontic attachments served as controls. GCF was sampled at 0, 1, 24, and 168 hours after initiation of treatment. Prevention of plaque-induced inflammation allowed assessment of the dynamics of mechanically stimulated SP levels in the GCF, which was determined using commercially enzyme-linked immunoabsorbent assay (ELISA) kits. GCF levels of SP for the Damon System sites were significantly lower than for the teeth with conventional brackets at 24 hours. This result indicates that the Damon System inhibited an increase in the amount of SP in the GCF. Thus, the Damon System is useful to reduce the inflammation and pain resulting from orthodontic forces. World J Orthod 2009;10:141–146.