There　is　an　urgent　need　to　search　for　novel　chemosensitizers　in　the　field　of　cancer　therapy.　Chlorogenic　acid　(CGA),　a　type　of　polyphenol　present　in　the　diet,　has　many　biological　activities.　The　present　study　is　designed　to　explore　the　influence　of　CGA　on　the　effects　of　5-fluorouracil　(5-FU)　on　human　hepatocellular　carcinoma　cells　(HepG2　and　Hep3B).　Treatment　with　5-FU　induced　the　inhibition　of　hepatocellular　carcinoma　cells＇　proliferation,　and　the　combined　treatment　with　CGA　enhanced　this　inhibition.　5-FU　also　increased　the　production　of　reactive　oxygen　species　(ROS).　The　combination　of　5-FU　and　CGA　led　to　a　more　prominent　production　of　ROS　and　significantly　inactivated　ERK1/2,　although　CGA　and　5-FU　exerted　no　significant　changes　when　used　alone.　A　previous　report　has　shown　that　ROS　are　upstream　mediators　that　inactivate　ERK　in　hepatocellular　carcinoma　cells.　Combined　with　our　results,　this　indicates　that　the　combination　of　5-FU　and　CGA　leads　to　the　inactivation　of　ERK　through　the　overproduction　of　ROS.　This　mediates　the　enhancement　of　5-FU-induced　inhibition　of　hepatocellular　carcinoma　cells＇　proliferation,　that　is,　CGA　sensitizes　hepatocellular　carcinoma　cells　to　5-FU　treatment　by　the　suppression　of　ERK　activation　through　the　overproduction　of　ROS.　CGA　has　shown　potential　as　a　chemosensitizer　of　5-FU　chemotherapy　in　hepatocellular　carcinoma.　Copyright　(C)　2015　Wolters　Kluwer　Health,　Inc.　All　rights　reserved.