Context: Adipokines actuate chronic, low-grade inflammation through a complex network of immune markers but the current understanding of these networks is incomplete. The soluble isoform of the interleukin-1 receptor accessory protein (sIL1RAP) occupies an important position in the inflammatory pathways involved in obesity. The pathogenetic and clinical influences of sIL1RAP are unknown. Objective: To elucidate whether plasma levels of sIL1RAP are reduced in obesity, using affluent clinical, biochemical and genetic data from two diverse cohorts. Design, Setting and Participants: The study was conducted in two cohorts - the San Antonio Family Heart Study (n = 1,397 individuals from 42 families) and South Asians living in Mauritius n = 230). Main outcome measures: Plasma sIL1RAP levels were measured using an enzyme-linked immunosorbent assay. The genetic basis of sIL1RAP levels were investigated using both a large scale gene expression profiling study and a genome-wide association study. Results: A significant decrease in plasma sIL1RAP levels were observed in obese subjects even after adjustment for age and sex. sIL1RAP levels demonstrated a strong inverse association with obesity measures in both populations. All associations were more significant in females. Plasma sIL1RAP levels were significantly heritable, correlated with IL1RAP transcript levels (NM 134470), showed evidence for shared genetic influences with obesity measures and were significantly associated with the rs2885373 SNP (p=6.7 x 10(-23)) within the IL1RAP gene. Conclusions: Plasma sIL1RAP levels are reduced in obesity and can potentially act as biomarkers of obesity. Mechanistic studies are required to understand the exact contribution of sIL1RAP to pathogenesis of obesity.