Accumulated evidence has indicated that Ephrin A1 (EFNA1) is associated with angiogenesis and tumorigenesisin various types of malignancies, including colorectal cancer (CRC). In the current study, we performed anonline search using the public microarray database to investigate whether EFNA1 expression might be alteredin CRC tissues. We then conducted a case-control study including 306 subjects (102 cases and 204 well-matchedcontrols) in Xiaoshan County to assess any association between genetic polymorphisms in EFNA1 and CRCsusceptibility. Searches in the Oncomine expression profiling database revealed EFNA1 to be overexpressed inCRC tissue compared with adjacent normal tissue. The rs12904 G-A variant located in the 3’ untranslated region(UTR) of EFNA1 was observed to be associated with CRC susceptibility. Compared with the AA homozygousgenotype, those carrying GA genotype had a decreased risk of developing CRC (odds ratio (OR) =0.469, 95%confidence interval (CI): 0.225-0.977, and P =0.043). The association was stronger among smokers and teadrinkers, however, no statistical evidence of interaction between rs12904 polymorphism and smoking or teadrinking on CRC risk was found. Our results suggest that EFNA1 is involved in colorectal tumorigenesis, andrs12904 A>G polymorphism in the 3’ UTR of EFNA1 is associated with CRC susceptibility. Larger studies andfurther mechanistic investigations are warranted to confirm our findings.