Epidemiological and experimental evidence from Western countries now consistently support an etiological role for human papillomavirus (HPV) in a subset of oropharyngeal squamous cell carcinomas (SCC), especially those originating in the tonsil. The role of HPV in the etiology of tonsil cancer in developing countries such as China has not been investigated. In this study, none of 16 tonsil cancer specimens from Chinese patients were positive for HPV DNA, whereas those from Australian patients using the same methodology gave a positivity rate of 46%. The tumors from Chinese patients, like the Australian HPV-negative subset, significantly overexpressed pRb and cyclin D1 and underexpressed p16(INK4A) (p16). In contrast, the Australian HPV-positive cancers overexpressed p16 and had reduced expression of pRb and cyclin D1. These findings may help explain why China has a relatively low rate of oropharyngeal cancer compared with Australia. They also support the hypothesis that molecular pathways to tonsil cancer mediated by HPV are distinct from those induced by mutagens present in cigarette smoke or alcohol.