Nasopharyngeal carcinoma (NPC) is rare in most parts of the world but occurs with high incidence in certain regions, such as South-East Asia. Two major histological types of NPC are recognized, non-keratinizing carcinoma and squamous cell carcinoma. Non-keratinizing NPCs, which include undifferentiated NPC, are invariably associated with Epstein-Barr virus (EBV) infection, regardless of the geographical or ethnic origin of the patients. By contrast, conflicting results have been published concerning a possible association of squamous cell NPC with the virus. To address this question, squamous cell NPCs have been collated from an area where NPC is endemic, Hong Kong, and from two regions where NPC occurs with a lower incidence, Chengdu, PR China, and Birmingham, United Kingdom. In situ hybridization for the detection of the small EBV-encoded nuclear RNAs (EBERs) demonstrated that all 22 cases from Hong Kong were EBV-positive. By contrast, EBV was detectable in 7 of 19 cases from central China, and in 3 of 7 cases from the U.K. Expression of the virus-encoded latent membrane protein 1 (LMP1) was detected in 3 of 32 EBV-positive squamous cell NPCs. These results indicate that the association of squamous cell NPCs with EBV shows geographical variability in a manner which is reminiscent of the situation encountered in Burkitt's lymphoma. This suggests that squamous cell NPCs are a pathogenetically heterogeneous group of tumours distinct from non-keratinizing NPCs.