Objectives: To assess the influences of the mutations within the long control region (LCR) and E2 open reading frame (ORF) of the human papillomavirus-2 (HPV-2) isolates from patients with extensive verrucae vulgaris with cutaneous horns in the activities of the viral early promoters. Methods: A PCR method was applied for screening HPV DNA in the lesion specimens and the complete HPV-2 genomes was analyzed. Recombinant CAT-reporter plasmids containing various HPV-2 LCRs and mammalian expression plasmids containing E2 ORF were constructed. The promoter activity was evaluated by transient transfection. Results: The whole HPV-2 genomes were obtained from both patients. Several mutations in LCR and mutations leading to alterations of amino acids in E2 protein were identified in isolate-1, while a few point mutations in LCR were seen in isolate-2. Under the control of LCRs, the viral early promoter activities of isolate-1 and isolate-2 were increased 3- and 2-fold, respectively. Alterations of amino acids in E2 protein of isolate-1 partially abolished its promoter repressive activity. Compared with that of prototype HPV-2, the promoter activity of isolate-1 in the presence of its E2-expressing plasmid was significantly increased. Conclusions: The increased promoter activities might be linked, at least partially, to the clinical phenotypes of the uncommon huge verrucae vulgaris. Copyright (c) 2007 S. Karger AG, Basel.