The human beta defensins (hBDs) 2 and 3 contribute to the inducible antimicrobial peptides in human skin. Besides an important role in fighting bacteria, they may also exert antiviral function. Verrucae vulgares and condylomata acuminata are typical cutaneous viral diseases caused by different subtypes of the human papillomavirus. Their tendency for spontaneous regression could be caused by antiviral proteins like defensins. In a retoperspective study, we investigated lesions of verrucae vulgares and condylomata acuminata for the presence of hBD-2 and hBD-3 by immunohistochemistry. All of the specimens of verrucae vulgares (n = 20) were positive for hBD-2 and hBD-3. The specimens of condylomata acuminata (n = 15) exhibited expression for hBD-2 and hBD-3, with the exception of three and two samples, respectively. The expression levels in condyloma acuminata were lower for both defensins compared with verrucae vulgares. Normal skin tissue exhibited no staining of both hBD-2 and hBD-3 with the exception of two cases. Taken together, this is the first report of an increased expression of the hBD-2 and hBD-3 in cutaneous papillomavirus infections.