Background— Inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of >60%, but to date few genetic variants influencing IL-6 levels are known. Methods and Results— We used the ITMAT-Broad-Care (IBC) HumanCVD disease BeadChip in the Whitehall II study (N=4911) and British Women’s Heart and Health Study (N=3445) to identify single-nucleotide polymorphisms associated with circulating IL-6 levels. Twenty-two single-nucleotide polymorphisms from 7 loci ( IL6R/TDRD10 , HLA-DRB1 , BUD13 , SEZ6L , IL1RN , TRIB3 , and ABO ) were associated with IL-6 ( P <10 ^–5 ), although none were associated with the IL6 gene itself. With the exception of TRIB3 , all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen single-nucleotide polymorphisms in the IL6R region in high-linkage disequilibrium (r ² >0.9) with a nonsynonymous variant, rs2228145, were also associated with IL-6 and C-reactive protein concentration ( P <10 ^–5 ). An IL-6–specific weighted allele score explained 2% of the variance of log IL-6 levels ( P =2.4410 ^–22 ) in Whitehall II and 1% ( P =1.910 ^–8 ) in British Women’s Heart and Health Studies. Conclusions— Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain single-nucleotide polymorphisms, exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signaling in a range of cardiometabolic diseases.