Pearly penile papules clinically resemble the sexually transmitted papular variant of genital condylomata. Histologically, however, pearly penile papules consist of fibropapillomata that lack the characteristic morphologic features of human papillomavirus (HPV) infection. To study the possible association of HPV infections with pearly penile papules, we examined tissue specimens from 13 men with pearly penile papules with and without associated penile condylomata. Biopsy specimens were tested for the presence of HPV DNA by the polymerase chain reaction. None of the pearly penile papules contained HPV DNA sequences, whereas four of seven cases clinically suspected of being condylomata associated with pearly penile papules contained HPV DNA. These results confirm that pearly penile papule lesions do not contain HPV DNA; therefore, the distinction between pearly penile papules and penile condylomata is clinically significant.