Interleukin-1 receptor antagonist concentration is upregulated in the plasma of patients with obese related disease, and its synthesis is under genetic control. We tested the hypothesis that the polymorphism in the interleukin-1 receptor antagonist gene second intron might be associated with normal weight obese syndrome. The polymorphism of intron 2 in the interleukin-1 receptor antagonist gene, containing a variable numbers of a tandem repeat (VNTR), and interleukin-1alpha and beta plasma levels were evaluated in 110 Caucasian Italian women, divided in three groups: non-obese, normal weight obese and preobese-obese. The allele 1 frequency was not significantly different in the three groups. The alleles 3 and 4 were not observed in any group. The allele 2 frequency in normal weight obese woman (12.5%) and preobese-obese (17.5%) groups were significantly different in comparison with the non-obese group (6.7%). The allele 5 was observed exclusively in non-obese and normal weight obese subjects (13.3 and 7.5%, respectively). In normal weight obese women, plasma concentrations of interleukin-1 alpha and interleukin-1 beta were significantly higher than in non-obese. The allele 2 was observed in normal weight obese as well as a significant association between the increase of interleukin-1 beta plasma amount and the allele 2 carrier. Our findings suggest that the allele 2 might be an important high-risk genetic marker for normal weight obese syndrome and obesity related diseases.