AbstractFAS rs2234767 (−1377 G>A), rs1800682 (−670 A>G) and FASLG rs763110 (−844 C>T) promoter polymorphisms can influence transcriptional activities of the genes and thus multiple tumors susceptibility. To investigate their association with risk of colorectal cancer (CRC), the three SNPs were genotyped in 878 cases and 884 controls and the results showed that the FAS rs2234767 and rs1800682 were in a high linkage disequilibrium (LD) with each other (D’ = 0.994) and jointly contributed to an increased risk of CRC (without vs. with rs2234767 GG/rs1800682 AA genotypes, adjusted OR = 1.30, 95% CI = 1.05 − 1.61). In vivo ChIP assays evaluated the effect of rs2234767 and rs1800682 on recruitment of SP1 and STAT1, respectively, to chromatin. The results showed SP1 interacting specifically with STAT1 recruited to their respective motifs for transcriptional activation. The mutant alleles rs2234767 A and rs1800682 G jointly affected coupled SP1 and STAT1 recruitment to chromatin. The interplay between SP1 and STAT1 was critical for the functional outcome of rs2234767 and rs1800682 in view of their high LD. In conclusion, the FAS rs2234767 and rs1800682 polymorphisms were in high LD with each other and they jointly contributed to an increased risk of CRC by altering recruitment of SP1/STAT1 complex to the FAS promoter for transcriptional activation.