Background: Recent studies indicate a strong functional relevance of the canonical inflammatory interleukin 6 signaling pathway in coronary artery disease (CAD). A genetic association of this signaling pathway with CAD has not been shown yet. We aimed to assess novel single nucleotide polymorphisms (SNPs) from genes of the Interleukin 6 signaling pathway. Results: To identify novel SNPs that are relevant for CAD, we employed a large-scale population-based case-control association study of 2199 cases and 1715 controls and assessed 73 SNPs from 12 genes out of the IL -6 signaling pathway. Results were adjusted to the CAD-related risk factors diabetes, hypertension, Body Mass Index, smoking and sex by logistic regres sion analysis. In a primary explorative study, we iden tified 5 SNPs that were significantly associated with CAD ( MAPK 1_rs6928, MAPK 1_rs9340, MAPK 1_ rs11913721, MAPK 14_rs7757672, JAK 1_rs310236). After adjustment to CAD-risk factors, MAPK 1_ rs6928 showed the strongest association with CAD (P 0.0217, Odds Ratio 1.36, Confidence Interval 1.05 - 1.77). To reproduce this result, we performed a replication study employing independent patient and control panels. In this study we could not approve the association of rs6928 with CAD. Conclusion: In conclusion, we did not detect significant associations of SNPs from the IL -6 signaling pathway with CAD. Our investigation demonstrates the importance of independent replication studies to verify results from candidate-gene association studies in the quest to discover the underlying pathomechanism of CAD.