The high temperature requirement factor A1 (HtrA1), a member of serine protease family, has been reported to be down-regulated in various cancer types and correlate with chemoresistance. However, the function of HtrA1 in colon cancer remains unclear. This study investigated the role of HtrA1 in cisplatin (CDDP) resistance of colon cancer. We found that HtrA1 was up-regulated in colon cancer cell line SW480 incubated with CDDP. By treating SW480 cells to a continuous exposure to CDDP, we developed CDDP-resistant SW480/CDDP cells and found that the mRNA and protein levels of HtrA1 were reduced. Besides, the stable knock-down of HtrA1 in SW480 transfected with HtrA1 shRNA could also induce chemoresistance against CDDP. To the contrary, ectopic expression of HtrA1 in SW480/CDDP cells abrogated CDDP resistance. The mechanism underlying HtrA-1 down-regulation induced chemoresisance was also investigated. In SW480/CDDP cells and SW480 cells with HtrA1 knock-down, X-linked inhibitor of apoptosis protein (XIAP) was increased, while the interfering of XIAP impeded CDDP resistance in SW480/CDDP cells. We also found that Akt was activated in SW480/CDDP cells and SW480 cells with HtrA1 knock-down. The inhibition of Akt activation reversed CDDP resistance. In conclusion, our results indicate that HtrA1 down-regulation induces CDDP resistance in colon cancer by increasing XIAP and activating PI3K/Akt pathway. This study provides evidence that HtrA1 might be a therapeutic target for overcoming CDDP resistance in colon cancer.