Serotonergic neurotransmitter system has been implicated in the pathogenesis of Alzheimer's disease (AD). 5-Hydroxytryptamine (5-HT)(6) receptor is mainly expressed in the brain areas involved in cognitive processes. And 5-HT(6) receptor gene (HTR6) variants may be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To assess whether HTR6 increases the risk for LOAD, we carried out an association study between the HTR6 polymorphism C267T and sporadic LOAD in Mainland Chinese. An association of C/T genotype with LOAD (OR = 2.10, P = 0.014) was observed. And no statistical difference was found between cases and controls after stratification for APOE epsilon4 status. These data suggest that the HTR6 polymorphism C267T possibly involved in the susceptibility to LOAD as an APOE epsilon4-allele independent risk factor of LOAD.