Chronic inflammation has been identified as an important component of the metabolic syndrome (MetS). Therefore, environmental and genetic factors contributing to the variation of inflammatory responses could affect individuals' susceptibility to MetS. We investigated the association between common IL1beta genetic polymorphisms, inflammation, and the MetS, and the modulation of diet-related variables (i.e., erythrocyte membrane fatty acid composition) in a white U.S. population. IL1beta single nucleotide polymorphisms (SNP) (-1473G > C, -511G > A, -31T > C, 3966C > T, 6054G > A), clinical and biochemical measurements were characterized in a total of 1120 subjects (540 males and 580 females) participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. The 6054 G > A SNP was significantly associated with plasma C-reactive protein (P = 0.054), adiponectin (P = 0.021), and the prevalence of MetS (P = 0.004). Moreover, there was a significant interaction between the 6054G > A SNP and erythrocyte membrane (n-3) PUFA (P = 0.019). Among subjects with low (n-3) PUFA content (below the median), the 6054 G allele was associated with increased risk of the MetS (OR = 3.29, 95%CI = 1.49-7.26 for GG and OR = 1.95, 95%CI = 0.85-4.46 for GA, P < 0.001) compared with the AA genotype, but there were no significant genotype associations among subjects with high (n-3) PUFA content (above the median). Further analyses supported a significant haplotype global effect on the MetS (P = 0.017) among subjects with low (n-3) PUFA content. These results suggested that IL1beta genetic variants were associated with measures of chronic inflammation and the MetS risk, and that genetic influences were more evident among subjects with low (n-3) PUFA intake.