BACKGROUND Serum amyloid A protein (SAA) is known as an inflammatory factor and an apolipoprotein that can replace apolipoprotein A-I/II components as the major apolipoprotein of high-density lipoprotein (HDL), which is related to atherosclerosis. The present study is aimed to evaluate whether the SAA gene polymorphism is involved in ischemic stroke in northern Chinese Han population. METHODS In a case-control study, the participants included 396 patients (239 males, 157 females) with ischemic stroke and 360 healthy subjects (211 males, 149 females). The rs12218 polymorphism of the SAA gene was analyzed by polymerase chain reaction and restriction fragment length polymorphism, while the rs2468844 polymorphism of the SAA gene was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS The frequencies of the CC genotype and the C allele of rs12218 were higher in participants with ischemic stroke than in the control group (P=0.020 in males, P=0.001 in large-artery atherosclerosis group, LAA). The frequencies of the AG genotype and the G allele of rs2468844 were higher in participants with ischemic stroke than in the control group (P=0.040 in males, P=0.011 in large-artery atherosclerosis group). Multiple logistic regression analysis revealed the significance of the rs12218 in males and in large-artery atherosclerosis group after adjustment for confounding factors. CONCLUSIONS The rs12218 polymorphism of the SAA gene was associated with ischemic stroke in males and in patients with large-artery atherosclerosis group in northern Chinese Han population.