Accumulating studies have evaluated the association of Alpha-2-Macroglobulin gene (A2M) 5 bp insertion/deletion (5 bp I/D, rs3832852) and Ile1000Val (rs669) polymorphisms with Alzheimer's disease (AD) risk, but the results remain inconclusive. To investigate whether these two polymorphisms facilitate the susceptibility to AD, we conducted a comprehensive systematic review and meta-analysis. Databases of PubMed, Embase, Web of Science, Medline, CNKI, and Google Scholar were searched to get the genetic association studies. All statistical analyses were conducted with Review Manager 5.2 and STATA11.0. Fifty-two articles were included in the final meta-analysis. We performed meta-analysis of 39 studies involving 8,267 cases and 7,932 controls for the 5 bp I/D polymorphism and 27 studies involving 6,585 cases and 6,637 controls for the Ile/Val polymorphism. Overall results did not show significant association between these two polymorphisms and AD risk in dominant, recessive, and multiplicative genetic models. On the stratification analyses by ethnicity and APOE ε4 status with genotypes of polymorphism sites, similar negative associations were found. The meta-analysis suggests that there is no enough evidence for associations of A2M gene polymorphisms (5 bp I/D, Ile1000Val) with AD risk at present, even after stratification by ethnicity and APOE ε4 with genotypes of polymorphism sites. However, due to the heterogeneity in the meta-analysis, the results should be interpreted with caution.