Background:Squamous cell papilloma is a benign mucosal disease associated with human papillomavirus. Its presence in human immunodeficiency virus (HIV)-infected patients has rarely been reported. Therapeutic modalities for oral squamous cell papilloma have limited success and recurrences are frequent in HIV-infected subjects. Imiquimod, is a topical immunomodulator successfully used in some human papillomavirus-related oral lesions. However, its use for oral squamous cell papillomas in HIV-infected individuals has never been described.Observations:We report two male adult patients with HIV-infection, B2 and C3 stage respectively, undergoing antiretroviral therapy, with multiple recalcitrant oral squamous cell papillomas, predominantly affecting the masticatory mucosa. These lesions were successfully treated with daily topical imiquimod 5% cream for a few weeks, with only mild and well-tolerated side effects. No recurrences were observed after a follow-up period of over 20 months.Conclusions:Our cases highlight the value of imiquimod for the non-invasive treatment of multiple persistent oral squamous cell papillomas in two HIV-infected patients.