AIMS: Polymorphisms in the RANTES (G-403A), monocyte chemoattractant protein-1 (MCP-1; A-2518G), stromal cell-derived factor-1beta (SDF-1beta; G801A), and C-C chemokine receptor-5 (CCR5; Delta32) genes have been associated with functional effects. These chemokines have been implicated in leucocyte recruitment to arterial lesions. In a case-control study, we explored relations between these polymorphisms and coronary artery disease (CAD), with respect to angiographic abnormalities and acute coronary syndromes (ACS). METHODS AND RESULTS: The LUdwigshafen Risk and Cardiovascular health (LURIC) cohort was genotyped by RFLP-PCR. Based on coronary angiography, individuals were sub-divided into CAD cases (n = 2694) and controls (n = 530). RANTES-403 genotype frequencies were significantly different in cases and controls (chi2 = 4.17, p = 0.041), as were A allele carrier frequencies (36.01% vs. 30.19%, OR = 1.30 [95%-CI = 1.06-1.60], p = 0.010). By multivariate analysis, RANTES A-403 retained significant association with CAD (chi2 = 8.40, p = 0.0038). RANTES A-403 was associated with increased ACS prevalence (OR = 1.36 [95%-CI = 1.08-1.71], p = 0.0073). MCP-1 G-2518, SDF-1beta A801, and CCR5 Delta32 were not associated with CAD. CONCLUSIONS: RANTES A-403 was associated with CAD independently from conventional risk factors and CRP or fibrinogen as inflammatory biomarkers. The association was enhanced in smokers and ACS, conditions where platelet activation and inflammation predominate. RANTES A-403 may increase genetic susceptibility to CAD.