502 Background: This study aimed to establish a correlation between the expression of cathepsin D; p53; Cox-2; EGFR; C-erbB2; Ki-67 protein and the prognosis of colorectal cancer patients. Methods: Tissue samples were collected from 266 patients who underwent surgery for colorectal cancer from January 2006 to December 2007. The expression of the six proteins was determined using immunohistochemical staining of paraffin-embedded tissue specimens. Results: Cathepsin D, p53, Cox-2, EGFR, C-erbB2, and Ki-67 expression was detected in 38.7%, 60.9%, 37.6%, 35.7%, 30.1%, and 74.4% of the samples, respectively. The expression of cathepsin D was significantly correlated with reduced cancer-free survival (p=0.036) and overall survival (p=0.003), whereas the expression of the other proteins could not be correlated. In a multivariate analysis, after adjusting for age, sex, and stage, cathepsin D expression was found to be an independent prognostic factor for a short overall survival(HR=8.55, 95% CI 1.07–68.49). Furthermore, patients with tumors expressing four or more of the proteins had a significantly decreased cancer-free survival rate (p=0.006) and overall survival rate (p=0.002), when compared with patients expressing fewer than four of the proteins Conclusions: In this study, the expression of CD was correlated with a poor prognosis in terms of the cancer-free survival and the overall survival rate. Importantly, the high hazard ratio (HR=8.55) associated with CD expression from the multivariate analysis, even after adjusting for the tumor stage, demonstrates its potential as an independent, single-gene prognostic factor. The expression of four or more of the examined proteins was significantly correlated with a poor prognosis, even after adjusting for the stage. Currently, the prognostic value of a single gene marker in CRCA is very controversial, but based on these results, we believe that the number of expressed genes/proteins may be helpful in identifying patients with both early-stage cancer and a potentially poor prognosis, which will help to determine if adjuvant chemotherapy is necessary.