To explore the effect of indomethacin on COX non-expressing colon cancer cells (HCT116 and SW480).We used MTT assay to assess the effect of indomethacin on the growth of the cultured cells. Transplanted tumor models were established with BALB/c nude mice and were treated with indomethacin at 3 mg/(kg x d) for 4 weeks. Tumor volume and mouse weight were recorded every other day. Histologic examination was performed.After 48-hour incubation with various concentrations of indomethacin, the growth of the two cell lines was significantly suppressed in a dose-dependent manner, with IC50 being (318.2 +/- 12.7) micromol/L and (701.4 +/- 29.5) micromol/L, respectively. Indomethacin also effectively retarded the tumor growth within xenografts by 44.6% according to the tumor volume. No obvious toxicity was observed in these nude mice.Indomethacin can inhibit the growth of COX-negative human colon cancer cells both in vitro and in vivo, which indirectly suggests that indomethacin exerts its anti-tumor effect at least partly independent of the cyclooxygenase inhibitory profile.