Abstract Background Krüppel-like factor 4 (KLF4) is involved in many important cellular processes such as growth, development, differentiation, proliferation, and apoptosis. The purpose of this study was to determine the significance of KLF4 in both tumors and normal tissues of patients with colorectal cancer (CRC). Methods Between January 2003 and June 2005, 125 patients with CRC receiving treatment at the Yonsei Cancer Center were selected. We examined the mRNA level of the KLF4 gene in primary CRC specimens and matched normal colon tissues using real-time RT-PCR. Correlation of survival with clinicopathological parameters, including KLF4 level, was investigated with univariate and multivariate analyses. Results CRC tissue had a significantly lower KLF4 level when compared with matched normal tissues (KLF4 in tumors: 2007 ± 1531 copies/μl, KLF4 in normal tissues: 6586 ± 2834 copies/μl; P <0.0001). However, there was a correlation between the KLF4 level in tumors and normal tissues. Patients with a high KLF4 level in matched normal tissues were more likely than those with a low KLF4 level to develop recurrence and had poorer overall survival (P = 0.005). Therefore, the KLF4 level in the normal tissue of individuals was associated with prognosis of individuals. Conclusions Our data suggest that KLF4 mRNA expression level in normal tissues and tumors may be a useful prognostic marker in patients with CRC.