Areca quid (AQ) chewing has been implicated an independent risk factor for the development of oral cancer. Taiwanese areca quid (AQ) refers to a combination of areca nut (AN), lime, and inflorescence of Piper betle Linn. (IPB) or Piper betle leaf (PBL). Studies of AQ in other countries reported that AN extract combined with lime generates reactive oxygen species (ROS), such as hydroxyl radical (HO.), known to be a contributing factor in oral mucosa damage. To determine whether HO. is formed in the oral cavity during AQ chewing, the formation of meta-tyrosine (m-Tyr) and ortho-tyrosine (o-Tyr) from l-phenylalanine (Phe) was confirmed. It was demonstrated that combined aqueous extracts of AN, lime, metal ions (such as Cu2+ and Fe2+), and IPB or PBL produced HO.. Thus, the yield of HO. significantly increases when higher amounts of IPB or lime are added and also when Cu2+ and Fe2+ are increased. Further, the omission of any one of these ingredients significantly reduces the formation of HO.. Our results found that chewing AQ with IPB generated significantly higher HO. than chewing AQ with PBL, and may result in greater oxidative damage to the surrounding oral mucosa.