Honokiol　is　a　hydroxylated　biphenyl　natural　product　and　displays　potent　antitumor　activity　against　several　cancers　including　prostate　cancer,　melanoma,　leukemia,　and　colorectal　cancer.　The　present　study　was　to　investigate　the　in　vitro　activity　of　honokiol　against　A549　and　95-D　human　lung　cancer　cells.A549　and　95-D　cells　were　used　with　honokiol　treatment.　Cell　viability　was　determined　by　CCK-8　assay.　The　cell　migration　and　apoptosis　were　evaluated　by　wound　healing　assay　and　TUNEL　staining　method　respectively.　The　expressions　of　ER-related　proteins　were　analyzed　by　western　blot　and　the　CHOP　siRNA　was　used　to　downregulate　the　CHOP　expression.The　results　demonstrated　that　treatment　of　A549　and　95-D　cells　with　honokiol　significantly　reduced　cell　viability　in　a　dose-　and　time-dependent　manner.　Furthermore,　honokiol　treatment　decreased　cell　migration　and　enhanced　cell　apoptosis,　which　is　accompanied　by　the　upregulation　of　the　expressions　of　ER　stress-induced　apoptotic　signaling　molecules　such　as　GRP78,　phosphorylated　PERK,　phosphorylated　eIF2α,　CHOP,　Bcl-2,　Bax,　and　cleaved　Caspase　9.　Honokiol　treatment-induced　increase　of　ER　stress-related　signaling　molecules　and　apoptotic　proteins　in　A549　and　95-D　cells　were　reversed　by　CHOP　siRNA.Collectively,　we　conclude　that　ER　stress　may　participate　in　the　action　of　the　anticancer　activity　of　honokiol　in　A549　and　95-D　cells　and　induction　of　ER　stress-related　apoptosis　may　represent　a　novel　therapeutic　intervention　for　human　lung　cancer.