Activation of microglia is a central part of the chronic inflammatory response in Alzheimer's disease (AD). Intercellular adhesion molecule‐1 (ICAM‐1) is a cell surface receptor that may act in AD to adhere microglia to beta amyloid fibrils within senile plaques. Preliminary evidence in an Italian population indicates that a polymorphism at codon 469 of the ICAM‐1 gene is a predisposing factor for sporadic AD. Another group has been unable to replicate this association in a Finnish population. A case‐control study utilizing a clinically well‐defined group of 283 sporadic AD patients and 283 control subjects was performed to test this association in an ethnically homogeneous population from Spain. The current study does not demonstrate any significant difference in E469K genotype or allele frequencies between AD patients and controls. Our study in the Spanish population argues against the hypothesis that polymorphism at codon 469 of the ICAM‐1 gene is causally related to AD. © 2003 Wiley‐Liss, Inc.