PURPOSE: Our recent report indicated that tumor suppressor gene (p53) mutations and protein aberrant expression were detected in pterygium. Inactivation of p53 by Human papillomavirus (HPV) 16/18 E6 plays a crucial role in cervical tumorigenesis. In this study, we further speculate that p53 inactivation may be linked with HPV infection in pterygium pathogenesis. To investigate the involvement of HPV 16/18 E6 in p53 inactivation in pterygium, the association between HPV 16 or HPV 18 infection, the HPV E6 oncoprotein, and p53 protein expression was analyzed in this study. METHODS: HPV 16/18 infection was detected by nested-polymerase chain reaction (nested-PCR), the p53 mutation was detected by direct sequencing, and the p53 and the HPV 16/18 E6 proteins were studied using immunohistochemistry on 129 pterygial specimens and 20 normal conjunctivas. RESULTS: The HPV 16/18 was detected in 24% of the pterygium tissues (31 of 129) but not in the normal conjunctiva, and the HPV16/18 E6 oncoprotein was detected in 48.3% of HPV 16/18 DNA-positive pterygium tissues (15 of 31). In addition, p53 protein negative expression in pterygium was correlated with HPV16/18 E6 oncoprotein expression but not with a p53 mutation. CONCLUSIONS: HPV 16/18 E6 contributes to HPV-mediated pterygium pathogenesis as it is partly involved in p53 inactivation and is expressed in HPV DNA-positive pterygium.