This study used case-control method to investigate roles of two alpha 2-macroglobulin (A2M) polymorphisms, a 5-bp insertion/deletion (A2M-I/D) and an A-->G substitution (A2M-A/G), in the development of sporadic Alzheimer disease (AD) in Mainland Han Chinese. Our results showed a trend of lower D-carrying genotype frequency in APOE-epsilon 4 carrying AD patients than in corresponding control subjects (chi(2)=3.67, p=0.055). The ID/AA genotype frequency was lower in AD patients comparing with controls (chi(2)=4.04, p=0.044). In AD patients, the G-carrying genotype frequency was significantly higher in APOE-epsilon 4 carrier subgroup than in APOE-epsilon 4 non-carriers (chi(2)=7.38, OR=2.99, 95% CI: 1.33-6.71, p=0.007). These results indicated that A2M-D allele was probably a weak AD protective factor, and there was a possible interaction of APOE-epsilon 4 and A2M-G alleles to increase AD risk in Mainland Han Chinese.