Elevated levels of periostin have been implicated as playing important roles in tumor invasion and metastasis in various tissues. Thus, we determined whether serum periostin levels were associated with progression and poor prognosis in colorectal cancer (CRC) patients. We measured serum periostin levels by ELISA in 67 CRC patients and 120 controls. We also evaluated periostin expression in human CRC specimens (n=15) using immunohistochemistry, and measured expression of periostin mRNA in 7 CRC tissue samples, matched normal tissues and in 4 colon cancer cell lines by RT-PCR. We analyzed the relationship between serum levels of periostin and other clinicopathologic characteristics in patients with CRC. The serum levels of periostin in CRC patients (40.9+/-15.4 ng/ml) were significantly elevated compared to that in healthy volunteers (21.0+/-7.3 ng/ml, P<0.0001) and benign colorectal polyps or adenomas (22.4+/-8.5 ng/ml, P<0.0001). Higher preoperative serum levels of periostin in CRC were found to correlate with distant metastasis (P=0.003), advanced-stage disease (stage III/IV, P<0.0001) and poor prognosis. Preoperative serum periostin levels of 15 cases were significantly higher than matched postoperative levels (47.2+/-13.5 ng/ml vs. 31.3+/-11.0 ng/ml, P=0.008). Twelve of 15 patients (80%) had positive immunohistochemical periostin staining in CRC samples. Interestingly, periostin mRNA was highly upregulated in CRCs in comparison with matched normal tissues, and no expression of periostin mRNA was detected in 4 colon cancer cell lines. Serum levels of periostin detected by ELISA may be of clinical value in identifying patients who may be at high risk for aggression and metastasis of CRC. Periostin may be produced by the stromal cells surrounding the tumor, but not by the CRC cells themselves.