In order to make a comprehensive assessment of the potential association between one genetic variant in the insulin receptor substrate 1 (IRS-1) gene, rs1801278, and colorectal cancer (CRC) risk, we conducted a meta-analysis of four epidemiological studies, which included 3,708 CRC cases and 4,176 controls. The data showed that rs1801278 polymorphism was not associated with increased CRC risk in the overall population. When stratifying by the race, the results showed that the rs1801278 polymorphism was associated with increased CRC risk under dominant model in mixed populations. Based on this meta-analysis, we conclude that the IRS-1 rs1801278 polymorphism might be a risk factor for CRC development in mixed populations. Further studies, either with larger sample size or involving other single nucleotide polymorphisms (SNPs) and haplotypes of the IRS-1 gene, are necessary to clarify the contribution of IRS-1 rs1801278 in colorectal carcinogenesis.