Background: This study aimed to determine the association between betel quid chewing and the occurrence of upper aerodigestive tract (UADT) cancers. Methods: A cohort of 17,388 subjects, recruited and interviewed over the 1990-2001 period, in Khon Kaen, Thailand, was followed up until 2011. The data were linked to the Khon Kaen Population-Based Cancer Registry. Results: The prevalence of betel quid chewing was 15.9%, with a female predominance (97.7%); the mean age of chewers was 57.7 years (SD 6.6). The overall incidence of UADT cancers from the cohort was 14.7 per 100,000 person-years, whereas the incidence among the chewers was 45.7. Betel nut chewing was the only major risk factor for UADT cancers in this population (HR=5.26, 95%CI=2.51-11.0), while weak associations were found for tobacco smoking and alcohol (HR=1.16, 95%CI=0.45-3.01 and 1.47, 95%CI=0.72-3.03 respectively). Conclusions: We found betel quid chewing to be a main risk factor for UADT cancers, resulting in a higher incidence in females. However, further study is required to explore the potential risk factors among non-chewers, non-smokers, and non-drinkers.