It has been reported that type I interferons (IFN-α/β) play an important role in innate immune responses against viral and bacterial infections. In this study, we used and examined naturally occurred canine periodontal disease to show the therapeutic efficacy of low dose oral administration (LDOA) of canine IFN-α subtype 4 (CaIFN-α4). We administered purified recombinant CaIFN-α4 expressed in a baculovirus system to dogs with or without gingival inflammation. We found that LDOA of CaIFN-α4 reduce periodontopathic bacterial counts. LDOA induced improvement of naturally occurring gingival inflammation, and reduction of the stress marker responses was also observed after LDOA. These results suggest that LDOA of CaIFN-α4 has effectiveness for improvement of naturally occurring gingival inflammation in dogs.