Killer-cell immunoglobulin-like receptors (KIRs) can regulate the activation and inhibition of nature killer (NK) cells by signal transduction. KIR genes are clustered in one of the most variable regions of human genome. To study colorectal cancer (CRC)-associated KIR genetic profiles, 119 patients were recruited and their KIR genotypes were determined by using polymerase chain reaction with sequence-specific primers. The KIR gene frequencies and genotypes of patients (CRC group) were compared with 97 Han Taiwanese from the Buddhist Tzu Chi Taiwan Marrow Donor Registry (Tzu Chi group). The gene frequencies of KIR2DL5B and KIR3DL1 in CRC group were significantly lower than that in Tzu Chi group (6.7% vs. 16.5%, P=0.023; 95.8% vs. 100%, P=0.041, respectively). Meanwhile, a lower frequency of full-length KIR2DS4 gene (KIR2DS4fl) was observed in CRC group, although not statistically significant (78.1% vs. 87.6%, P=0.069). There were 23 KIR genotypes identified in CRC group, 27 genotypes in Tzu Chi group, and 40 genotypes in total. On the other hand, CRC and Tzu Chi groups showed a similar 3:1 ratio of haplotypes A and B. Meanwhile, the frequencies of haplotype A/A in CRC and Tzu Chi groups were 53.8% and 52.6%, respectively. Whereas, a significantly lower frequency of KIR2DS4fl was observed in CRC patients with haplotype B/X compared with Tzu Chi group (69.1% vs. 87.0%, P=0.033). In addition, CRC patients with haplotype B/X showed better overall survive (OS) compared with those with haplotype A/A. The median OS surpassed 70 months in the haplotype B/X subgroup, while 34 months in the haplotype A/A subgroup (P=0.083). Taken together, KIRs modulate the immune surveillance in tumor microenvironment through regulation of NK cell development and activation. Accordingly, diverse KIR genetic profiles might serve as a prognostic factor in CRC.