Tobacco　smoke　and　human　papillomavirus　(HPV)　are　both　crucial　causes　of　cancer,　and　their　cooperative　carcinogenesis　has　drawn　more　attention　in　recent　years.　Apigenin　(AP),　a　typical　flavonoid　abundantly　found　in　flowers　of　plants,　vegetables,　and　fruits,　has　been　demonstrated　to　exert　an　anti-carcinogenic　effect　on　various　types　of　cancer.　In　this　study,　we　investigated　the　capability　of　AP　against　malignant　transformation　and　DNA　damage　of　immortalized　human　esophageal　epithelial　(SHEE)　cells　induced　by　the　synergism　of　HPV18　and　4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone　(NNK).　The　results　indicated　that　the　enhancement　of　migration,　invasion,　and　proliferation　ability　of　SHEE　cells　induced　by　HPV　and　NNK　could　be　effectively　inhibited　by　AP.　Moreover,　the　levels　of　pyridyloxybutylated　(POB)-DNA　adducts　induced　by　NNK　via　P450-catalyzed　metabolic　activation　could　also　be　significantly　suppressed　by　AP.　Further　analyses　on　the　molecular　mechanism　revealed　that　AP　inhibited　the　synergistic　carcinogenesis　of　NNK　and　HPV　on　SHEE　cells　by　reducing　the　expression　of　mutp53,　CDK4,　Cyclin　D1,　and　p-Rb　(Ser　780),　increasing　caspase-3　activity,　thereby　arresting　the　cell　cycle　at　G1　phase　and　promoting　apoptosis　of　SHEE　cells.　We　hypothesize　that　the　decrease　in　NNK-induced　POB-DNA　adduct　levels　is　related　to　the　deactivation　of　P450　by　AP,　which　needs　to　be　confirmed　in　future　studies.　This　study　highlights　that　AP　may　be　employed　as　a　promising　chemopreventive　agent　against　cancers　in　smokers　with　an　HPV　infection.