The　use　of　non-steroidal　anti-inflammatory　drugs　(NSAIDs)　has　been　associated　with　a　reduced　risk　of　various　types　of　cancer,　including　esophageal　cancer.　However,　the　mechanisms　underlying　the　antineoplastic　effects　of　NSAIDs　in　esophageal　cancer　remain　to　be　elucidated.　In　the　present　study,　a　significant　inhibition　in　cell　viability　was　observed　in　the　EC109　cells　following　treatment　with　different　concentrations　of　indomethacin,　and　these　effects　occurred　in　a　dose-　and　time-dependent　manner.　This　inhibition　was　due　to　the　release　of　second　mitochondria-derived　activator　of　caspase　(Smac)　into　the　cytosol　and　the　activation　of　caspase-3.　Subsequently,　flow　cytometry　was　performed　to　investigate　indomethacin-induced　apoptosis　following　the　overexpression　or　knockdown　of　Smac,　and　western　blot　analysis　was　performed　to　determine　the　expression　of　Smac　and　the　activation　of　caspase-3.　Overexpression　of　Smac　was　promoted　apoptosis,　while　downregulation　of　Smac　significantly　inhibited　apoptosis.　Western　blot　analysis　demonstrated　that　indomethacin　induced　apoptosis　through　releasing　Smac　into　the　cytosol　and　activating　caspase-3.　These　results　indicated　that　Smac　is　essential　for　the　apoptosis　induced　by　indomethacin　in　esophageal　cancer　cells.