The aim of this study is to investigate the associations between KAI1/CD82 gene polymorphisms and colorectal cancer (CRC)-risk predisposition. We undertook a case-control study to analyze two KAI1/CD82 polymorphisms (exon 3 -29166 C>T and exon 9 -52840 C>A) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 356 patients with CRC and 378 control participants, and performed KAI1/CD82 genotyping using DNA sequencing. The obtained results indicated that overall, no statistically significant association was observed in exon 9 (-52840 C>A). Nevertheless, exon 3 (-29166 C>T) genotype was at increased risk of CRC (P = 0.006; odds ratio = 1.299, CI 95% 1.058-1.549). Furthermore, -29166 T allele CRCs were more significantly common in patients with tumor size of >4 cm than C allele CRC and in cases of poor differentiation and advanced pathological stage. These findings led us to conclude that polymorphism in exon 3 (-29166 C>T) was observed to be associated with susceptibility of CRC. However, exon 9 (-52840 C>A) polymorphism showed no correlation to CRC susceptibility. Nevertheless, further investigation with a larger sample size is needed to support our results.