Alzheimer disease (AD) is the most common neurodegenerative disease, and inflammation has been associated with the pathogenesis of AD. The myxovirus resistance protein 1 (MxA) is an interferon-induced antiviral protein and is widely studied in virus-caused diseases. An immunohistochemical study has shown MxA expression in senile plaques of the AD brain, suggesting that MxA might be involved in the pathogenesis of AD. In this study, 10 tagged single-nucleotide polymorphisms (SNPs) and two commonly studied SNPs in the MxA gene were investigated in 220 AD patients and 316 age-matched healthy Chinese subjects to investigate the association to the predisposition and age of onset (AAO) of AD. Healthy subjects were followed up for 2 years to determine the association of MxA polymorphisms and the rate of cognitive deterioration. Our result showed rs17000900 (MxA-123) and rs461093 were significantly associated with the risk of AD. Six MxA SNPs, including MxA -123, were associated to AAO of AD. The carriers of minor alleles of five MxA SNPs, including rs457274, rs2071430 (MxA -88), rs461093, rs469083, and rs1557372, were associated with faster cognitive decline over 2 years. Furthermore, our functional assay showed significant association between increased MxA expression and the -123A/-88T haplotype, which is in line with our findings in genetic association. This is the first study showing the significant association of MxA SNPs and predisposition of AD, modulation of AAO in AD, and rate of cognitive decline.