BACKGROUND The cluster of differentiation 33 (CD33) gene is compelling among the susceptibility genes of Alzheimer's disease (AD) in Genome-wide association study (GWAS). Researches of the relationship between AD and polymorphism in CD33 have showed conflicting results. In order to more precisely evaluate whether CD33 variants are associated with AD, we performed the meta-analysis presented in this manuscript. METHODS We searched from three databases including PubMed, Cochrane library and EMbase for related case-control researches based on criteria of determination. A total of 18 case-control studies, containing 50,030 cases and 77,405 controls were involved in CD33 rs3865444 polymorphism. And a total of 4 case-control studies, containing 826 cases and 984 controls were involved in CD33 rs3826656 polymorphism. RESULTS This study demonstrated that different variants in CD33 were associated with AD (rs3865444: OR =0.94; 95% CI, 0.90-0.98, P<0.01; rs3826656: OR =0.94; 95% CI, 0.62-1.41, P<0.01). We made subgroup analysis which was stratified by race. There were protective associations in Caucasians but not in Asians among CD33 rs3865444 polymorphism (Caucasians: OR =0.92; 95% CI, 0.90-0.94, P=0.05; Asians: OR =0.87; 95% CI, 0.65-1.17, P<0.01). CONCLUSIONS The CD33 rs3865444 polymorphism could be a protective factor in AD. Meanwhile, there was no association between the CD33 rs3826656 polymorphism and AD. Further confirmation is needed in larger and better-designed researches.