Context: Interleukin-6 (IL6) is immune-modulating cytokine associated with obesity in humans. Objective: To assess the associations between the genetic variability of IL6 gene and adiposity and long-term changes.Design and Subjects: We determined the LD-tagging SNPs of IL6 gene in 2255 healthy women and 980 healthy men from two prospective cohorts. We also conducted a meta-analysis on the associations between polymorphism -174G>C (rs1800795) and adiposity. Results: IL6 haplotype 222211 (possessing rs2069827, rs1800797, rs1800795, rs1554606, rs2069861, and rs1818879; "1" codes the common and "2" codes the minor alleles) was consistently and significantly associated with greater waist circumference (P=0.009 in men P=0.0003 in women) and baseline BMI (P=0.01 in men and P=0.046 in women) compared with the most common haplotype 111112. Haplotype 222211 was also associated with significantly higher early adulthood BMI in women (P=0.007). The haplotype-associated difference in BMI persisted significantly during the follow-up. A 5' promoter polymorphism rs2069827 was consistently associated with significantly higher early adulthood BMI, baseline BMI and waist circumference in men (carriers vs noncarriers, P=0.01, 0.007, and 0.008) and women (P=0.01, 0.10, and 0.0016). The data from this study and a meta-analysis of 26,944 individuals did not support substantial relations between the best-studied polymorphism -174G>C and adiposity. Conclusions: Our data from two independent cohorts indicate the variability of IL6 gene is significantly associated with adiposity. Such associations are less likely caused by polymorphism -174G>C.