Human Papillomavirus infection is considered as the main etiological factor of cervical cancer (ICC), although, the role of host genetic factors in ICC susceptibility has been increasing. Immunological response is crucial for the prevention of viral associated diseases. Interleukin 1 receptor antagonist (IL-1RN) is considered to be an important regulator of host immunity and several studies have shown a potential role of a 86 bp VNTR polymorphism within intron 2 of the IL-1RN gene in host immune response variability. We investigated the role of this polymorphism in cervical cancer development in Portugal with a case-control study developed with peripheral blood samples from 196 healthy women and 340 women with cervical lesions from the Northern Region of Portugal. We observed that IL-1RN Allele 2 homozygosis was significantly higher in cases than in controls. In fact, IL-1RN A2*A2 homozygous revealed to be associated with an increased risk of HSIL + ICC (OR = 1.90; 95 % IC 1.13-3.21; p = 0.015). Furthermore, we also observed that median age of onset of HSIL + ICC was significantly different (46.0 vs 52.0) in IL-1RN A2*A2 homozygous comparing to non-A2*A2 (p = 0.028). Our results indicated that IL-1RN A2 allele is associated with an increased susceptibility to cervical cancer development, probably by increasing predisposition to shorter immune responses.