Background: NPR3, located on human chromosome 5 (5p14-p13), encodes the natriuretic peptide receptor type C (NPR-C) that is mainly known as the natriuretic peptide clearance receptor. Involvement of NPR3 in susceptibility to cardiovascular diseases, i.e. hypertension, has been previously shown. With regard to stroke predisposition, evidence for a potential role of genetic variation within or nearby NPR3 has been suggested by a previous genome wide association study. Methods: We investigated the contribution to early-onset ischemic stroke susceptibility of the NPR3 -55 C>A transition by genotyping this variant in an Italian cohort of 368 cases and 335 controls. Results: In a multivariable logistic regression analysis adjusting for age, gender, hypertension, hypercholesterolemia, smoking habit and diabetes, a significant association of the -55 AA genotype with stroke was observed (OR=3.2, 95% CI 1.2-8.3, p=0.016). Remarkably, the polymorphism remained associated with stroke after adjusting for hypertensive status. Conclusion: Our observation obtained in an Italian cohort of early onset ischemic strokes suggests that a NPR3 promoter gene variant could have a role on cerebrovascular disease susceptibility. (C) 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.