Introduction.　Chlorpyrifos　(CPF)　is　a　organophosphate　insecticide　widely　used　in　agriculture　with　attendant　adverse　health　outcomes.　Chronic　exposure　to　CPF　induces　oxidative　stress　and　elicits　harmful　effects,　including　hepatic　dysfunction.　Molecular　hydrogen　has　been　identified　as　a　novel　antioxidant　which　could　selectively　scavenge　hydroxyl　radicals.　Objective.　The　aim　of　this　study　was　to　determine　whether　the　intake　of　hydrogen-rich　water　(HRW)　could　protect　rats　from　hepatotoxicity　caused　by　sub-chronic　exposure　to　CPF.　Materials　and　method.　Rats　were　treated　with　hydrogen-rich　water　by　oral　intake　for　8　weeks.　Biochemical　indicators　of　liver　function,　SOD　and　CAT　activity,　GSH　and　MDA　levels　were　determined　by　the　spectrophotometric　method.　Liver　cell　damage　induced　by　CPF　was　evaluated　by　histopathological　and　electron　microscopy　analysis.　PCR　array　analysis　was　performed　to　investigated　the　effects　of　molecular　hydrogen　on　the　regulation　of　oxidative　stress　related　genes.　Results.　Both　the　hepatic　function　tests　and　histopathological　analysis　showed　that　the　liver　damage　induced　by　CPF　could　be　ameliorated　by　HRW　intake.　HRW　intake　also　attenuated　CPF　induced　oxidative　stress,　as　evidenced　by　restored　SOD　activities　and　MDA　levels.　The　results　of　PCR　Array　identified　12　oxidative　stress-related　genes　differentially　expressed　after　CPF　exposure,　8　of　chich,　including　the　mitochondrial　Sod2　gene,　were　significantly　attenuated　by　HRW　intake.　The　electron　microscopy　results　indicated　that　the　mitochondrial　damage　caused　by　CPF　was　alleviated　after　HRW　treatment.　Conclusions.　The　results　obtained　suggest　that　HRW　intake　can　protect　rats　from　CPF　induced　hepatotoxicity,　and　the　oxidative　stress　signaling　and　the　mitochondrial　pathway　may　be　involved　in　the　protection　of　molecular　hydrogen.　©　2020,　Institute　of　Agricultural　Medicine.　All　rights　reserved.