Acute coronary syndromes (ACSs) are associated with both systemic inflammatory activation and endothelial cell activation, and both of these are linked to patient outcome. Genetic variation at the interleukin-1 (IL-1) locus influences the clinical patterns of inflammatory disease. We therefore examined the association between IL-1 gene polymorphisms and levels of systemic inflammatory activation markers [C-reactive protein (CRP) and IL-1 receptor antagonist (IL-1ra)] and of soluble endothelial activation markers [von Willebrand factor (vWF) and E-selectin], in a cohort of 63 patients presenting with non-ST-elevation ACS. The IL-1 locus did not significantly influence any of the markers studied at 24 h after presentation. Associations of IL-1 polymorphisms with the changes (Delta) in CRP, IL-1ra, E-selectin and vWF levels between 24 and 48 h were examined in later studies. Delta CRP and Delta IL-1ra showed no significant association with any of the polymorphisms studied. There was a strong association between carriage of the rare allele (allele 2) of the intron 2 variable number of tandem repeats polymorphism of IL-1RN (designated IL-1RN*2) and Delta E-selectin levels: [carriage of *2, 3.03 ng/ml [95% confidence interval (CI) 6.26 to 1.51 ng/ml]; non-carriage of *2, 0.12 ng/ml (95% CI 1.07 to -1.76 ng/ml); P=0.0016], and also between carriage of IL-1RN*2 and Delta vWF levels [carriage of *2, 0.78 i.u./ml (95% CI 0.96 to 0.44 i.u./ml); non-carriage of *2, 0.1 i.u./ml (95% CI 0.19 to -0.1 i.u./ml); P=0.0003]. A composite analysis consisting of carriage of IL-1RN*2 and the genotype at position -511 in the IL-1B gene suggests the existence of haplotypes that influence Delta vWF and Delta E-selectin in patients with ACS. Carriage of IL-1RN*2 was also associated with a 2-fold increased likelihood of a troponin-positive status compared with non-carriage (P=0.0385). These data indicate that, in the setting of non-ST-elevation ACS, genetic variation at the IL-1 gene locus contributes to the changes in soluble markers of endothelial inflammation.