Purpose:　Celecoxib,　an　inhibitor　of　cyclooxygenase-2　(COX2),　was　investigated　for　enhancement　of　chemotherapeutic　efficacy　in　cancer　clinical　trials.　This　study　aimed　to　determine　whether　celecoxib　combined　with　5-fluorouracil　or　sorafenib　or　gefitinib　is　beneficial　in　HepG2　multicellular　spheroids　(MCSs),　as　well　as　elucidate　the　underlying　mechanisms.　Methods:　The　human　hepatocellular　carcinoma　cell　line　HepG2　MCSs　were　used　as　in　vitro　models　to　investigate　the　effects　of　celecoxib　combined　with　5-fluorouracil　or　sorafenib　or　gefitinib　treatment　on　cell　growth,　apoptosis,　and　signaling　pathway.　Results:　MCSs　showed　resistance　to　drugs　compared　with　monolayer　cells.　Celecoxib　combined　with　5-fluorouracil　or　sorafenib　exhibited　a　synergistic　action.　Exposure　to　celecoxib　(21.8　mu　mol/L)　plus　5-fluorouracil　(8.1　x　10(-3)　g/L)　or　sorafenib　(4.4　mu　mol/L)　increased　apoptosis　but　exerted　no　effect　on　COX2,　phosphorylated　epidermal　growth-factor　receptor　(p-EGFR)　and　phosphorylated　(p)-AKT　expression.　Gefitinib　(5　mu　mol/L),　which　exhibits　no　growth-inhibition　activity　as　a　single　agent,　increased　the　inhibitory　effect　of　celecoxib.　Gefitinib　(5　mu　mol/L)　plus　celecoxib　(21.8　mu　mol/L)　increased　apoptosis.　COX2,　p-EGFR,　and　p-AKT　were　inhibited.　Conclusion:　Celecoxib　combined　with　5-fluorouracil　or　sorafenib　or　gefitinib　may　be　superior　to　single-agent　therapy　in　HepG2　MCSs.　Our　results　provided　molecular　evidence　to　support　celecoxib　combination-treatment　strategies　for　patients　with　human　hepatocellular　carcinoma.　MCSs　provided　a　good　model　to　evaluate　the　interaction　of　anticancer　drugs.