Human papillomavirus (HPV) infection in the normal oral cavity was studied by the sensitive polymerase chain reaction (PCR) using primers for the L1 region of human papillomavirus DNA and high fidelity amplification system. Cells were scraped from the oral mucosae of 7 (mean age; 42 years) and 30 (mean age; 32 years) volunteers with and without skin warts, respectively. Human papillomavirus DNA was detected in 30/37 (81.1%) specimens and their copy numbers per cell were 10(-1) to 10(-4) (mean, 10(-3)). The human papillomavirus types determined by PCR-based sequencing analysis were HPV-18 (26/30; 86.7%), -61 (18/30; 60%), -59 (7/30; 23.3%), -16 (2/30; 6.7%), -6 (1/30; 3.3%) and an unknown type (HPV-X71) (1/30; 3.3%). Multiple human papillomavirus types were present in 17/30 (56.7%) specimens. HPV-6 was detected in 2 of 7 skin warts and differed from the human papillomavirus types of the corresponding oral specimens. These data suggest that human papillomavirus infection in the oral mucosa occurs much more frequently than previously considered.