Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a central role in the pathogenesis of stroke. A base pair substitution -174G/C in the promoter region of the IL-6 gene regulates IL-6 gene expression. We compared the prevalence of this polymorphism in patients with lacunar stroke and in an age- and sex-matched cohort of asymptomatic controls. Eighty-two patients with lacunar stroke and 82 asymptomatic controls were prospectively assessed and genotyped for the -174G/C polymorphism in the promoter region of the IL-6 gene. Demographics and vascular risk factors were recorded in both groups. A brain computed tomography scan/magnetic resonance imaging confirmed the clinical diagnosis of lacunar stroke in all patients. The prevalence of CC genotype (18.3 vs. 7.3%, P=0.03), and the frequency of C allele (42.7 vs. 31.1%, P=0.03) were statistically significantly higher in patients with lacunar stroke than in asymptomatic controls. Expectedly, patients with lacunar stroke had a higher prevalence of vascular risk factors than asymptomatic controls. A logistic regression model showed that independent variables associated with lacunar stroke included history of hypertension (odds ratio (OR), 7.02; 95% confidence interval (95% CI), 3.11-15.81), diabetes (OR, 5.37; 95% CI, 1.52-8.89), hyperlipidemia (OR, 3.43; 95% CI, 1.04-11.25), smoking (OR, 5.84; 95% CI, 2.15-15.84), and CC genotype of the -174G/C IL-6 gene polymorphism (OR, 4.28; 95% CI, 1.22-15.00). These findings suggest that lacunar stroke might result from genetic susceptibility to inflammation-mediated damage in concert with atherosclerotic risk factors.