Peripheral blood neutrophils from periodontitis patients exhibit a hyperreactive and hyperactive phenotype (collectively termed hyperresponsivity) in terms of production of reactive oxygen species (ROS). The molecular basis for this phenomenon, however, has yet to be determined. Our objectives were to identify genes differentially expressed in hyperresponsive peripheral blood neutrophils from chronic periodontitis patients relative to periodontally healthy controls and use these data to identify potential contributory pathways to the hyperresponsive neutrophil phenotype. Using microarray technology we demonstrated differential expression of 163 genes (149 increased, 14 decreased) representing a range of ontological classes. There was increased expression of a significant number of IFN-stimulated genes (ISG). RT-PCR analysis of ISG transcripts in individual and pooled samples further corroborated these data, and indicated that levels decreased to near those of controls following successful therapy. Significantly enhanced FcgammaR-stimulated ROS production was subsequently achieved by priming control neutrophils with IFN-alpha/-beta/-gamma, but not LPS, and gene expression analysis indicated that exposure to the type I IFN (in particular IFN-alpha) better replicated the mRNA profile observed in vivo. Further studies demonstrated that plasma levels of IFN-alpha were significantly higher in samples from patients relative to unaffected controls. Following successful periodontitis treatment, plasma IFN-alpha levels, neutrophil ISG expression, and FcgammaR-stimulated neutrophil ROS output of patients, all decreased to levels comparable with those of controls. In conclusion, although chronic periodontitis is a complex disease, raised IFN-alpha may be one determinant of the distinct molecular phenotype and hyperresponsivity exhibited by patients' peripheral blood neutrophils.