Activation of microglia is a central part of the chronic inflammatory process in Alzheimer disease (AD). The monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays a role in microglial migration and accumulation at sites of beta-amyloid deposition in senile plaques in the AD brain. A polymorphism in the regulatory region (-2518) of the MCP-1 gene affects the level of MCP-1 expression, and has been associated with a stronger inflammatory response and higher peripheral tissue damage in chronic inflammatory diseases. We investigated whether the MCP-1 (-2518) polymorphism might be responsible for susceptibility to AD in a large Spanish population, utilizing a clinically well-defined group of 328 sporadic AD patients and 315 control subjects. We also examined the combined gene effects between MCP-1 and other proinflammatory cytokine genes such as interleukin-1A (IL-1A) and tumor necrosis factor-alpha (TNF-alpha), and the apolipoprotein E (APOE) gene. In the present study, neither the MCP-1 (-2518) G allele itself nor its interaction with the IL-1A (-889) allele 2, TNF-alpha (-850) allele T or APOE epsilon4 allele conferred increased risk for AD.