MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate target gene expression at the posttranscriptional level. Although recent studies have indicated that miR-146a is involved in the tumorigenesis of various types of malignancies, few studies have investigated its role in colorectal cancer. In the current study, we examined the expression of miR-146a in colorectal cancer tissue and adjacent normal controls using publicly available expression profiling data. We then conducted a population-based case-control study which included 554 colorectal cancer cases and 566 matched healthy controls to assess the association of a genetic variant (rs2910164) in miR-146a with colorectal cancer susceptibility. We observed decreased expression of miR-146a in rectal cancer tissue compared with adjacent normal controls (P < 0.001). Association between miR-146a rs2910164 polymorphism and risk of colorectal cancer was detected with effect modification by alcohol drinking status (P for interaction = 0.010). Among non-alcohol drinkers, individuals with CC/CG genotype had an increased risk of developing colorectal cancer compared with those carrying GG genotype (odds ratio (OR) = 1.63, 95 % confidence interval (CI): 1.07 ∼ 2.47). Our findings indicate an association between miR-146a dysregulation and colorectal cancer, and suggest that miR-146a may play a role in colorectal carcinogenesis. Further large population-based prospective studies as well as mechanistic investigations are warranted to validate our findings.