Aural plaques affect at least 22% of horses and can be asymptomatic or cause ear sensitivity. Immunohistochemical and electron microscopy studies have shown a strong association between aural plaques and papilloma virus. The purpose of this study was to investigate the efficacy of imiquimod 5% cream, an immune response modifier with potent antiviral activity, in the treatment of equine aural plaques. Twenty-one horses were enrolled and 16 completed the study. Imiquimod 5% cream was applied three times a week, every other week. When both ears were affected only the worst affected ear was treated. Adverse effects in all horses included marked local inflammation, exudation and thick crust formation at the site of treatment and the adjacent skin. Removal of the crust before treatment was painful and required sedation in most horses. Complete resolution of lesions was noted in all horses immediately post-treatment and the long-term resolution rate was 87.5%. Duration of therapy ranged from 1.5 to 8 months (median: 2.9 mean: 3.5). All horses were followed-up for 12-22 months after treatment was discontinued and only two horses had a recurrence of lesions. Clinical signs related to the aural plaques prior to treatment were reported in 11 of 16 (68.8%) horses and included resistance to touching the ears and bridling. Complete resolution of these signs was reported by the owners in all of the horses followed-up for at least 12 months. In conclusion, the topical application of imiquimod 5% cream is an efficacious treatment for aural plaques in horses.