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Canine oral papillomatosis (COP) is the most common self-limiting neoplastic disease in dogs, caused by the canine oral papillomavirus (COPV). Despite its tendency toward spontaneous regression, treatment of oral papilloma cases is essential due to the physical difficulties animals experience when ingesting food, restrictions on social interaction with other dogs, as well as the occurrence of anorexia, sialorrhea, halitosis, bleeding, secondary bacterial infections, and purulent discharge adjacent to the papillomas. In dogs, azithromycin is used for the treatment of several bacterial conditions and has a favorable safety profile. Based on previous reports and clinical observations, the hypothesis was raised that this drug could be associated with lesion regression in cases of canine oral papillomatosis. In this case report, the clinical course of a dog that underwent surgical removal of the lesions followed by azithromycin administration is described, in which complete regression of the lesions was observed during the follow-up period. The findings are presented as an initial clinical observation, reinforcing the need for controlled studies to evaluate the therapeutic efficacy of azithromycin in canine oral papillomatosis.