Condylomata acuminata (CA) caused by human papillomavirus (HPV) is a common sexually transmitted disease with half a million new cases diagnosed in the United States per year and the annual increase in incidence in China. Recurrence is a major challenge for CA treatment. Recently, we demonstrated that FOXP3(+) regulatory T (Treg) cells mediate the immunosuppression in large genital warts. Here, we further report that low-dose cyclophosphamide (CY), a conventional chemotherapy drug, can effectively prevent the recurrence of large CA in clinical patients after laser therapy. Surprisingly, although 9 out of 52 patients recur six weeks after the combination treatment, the re-administration of low-dose CY alone completely eliminates most recurred lesions. We provide evidence that low-dose CY not only depletes patients' Treg cells and enhances function of HPV-specific T cells and NK cells in the periphery, but also ameliorates the immune milieu of the lesion site, leading to the elimination of remnant viruses. These findings have important clinical significance, and potentially lead to a therapeutic breakthrough for the treatment of CA. (C) 2010 Elsevier Inc. All rights reserved.