This study examined the association of IL1 genetic polymorphisms (IL-1A +4845, IL-1B +3954 & IL-1RN +2018) with periodontal disease status of Down syndrome (DS) individuals. Fifty-four DS patients (18-56 yr, 48.15% male, 77.78% Caucasians) were recruited from the Georgia Regional Hospital (GRH) health care system. Two comparable groups (71 mentally retarded patients and 87 control subjects) were also recruited. All subjects were nonsmokers. Periodontal evaluations (plaque index, gingival index, bleeding-on probing and clinical attachment levels (AL)), personal and professional dental care habits were recorded. Blood was collected by a venipuncture. The IL-1A +4845, IL-1B +3954 & IL-1RN +2018 loci were genotyped by the TaqMan assay. No statistically significant differences were noted in the distribution of IL-1 gene polymorphisms between the three groups. The IL-1 variant genotypes varied by race; for both IL-1A and IL-1RN, the variant gene was significantly more prevalent among whites than non-whites (ps > 0.1). ANCOVA, which also adjusted for age, showed a 3-way interaction among dental visits, gene variation and Down status [(F(1, 179) = 3.96, P = 0.048 in White subjects and F(1, 241) = 2.96, P = 0.087 in all subjects). Post-hoc t-tests confirmed lower levels of AL in IL-1RN-variant Down subjects receiving more frequent dental visits (P < 0.05). ANCOVA, which also adjusted for age, showed an interaction between IL-1A/B gene variation and Down status (F(1, 174) = 3.04, P = 0.083 in White subjects and F(1, 235) = 3.72, P = 0.055 in all subjects). Post-hoc t-tests confirmed lower levels of AL in IL-1A/B-variant Down subjects (P < 0.05). The distribution of variant IL-1 genes in DS subjects was not different from the general population. However the association between the carriage of the IL-1 rare alleles and periodontitis differed between the Down and non-Down subjects. The carriage of the IL-1 rare alleles in the Down subjects tended to confer a protective effect against loss of periodontal attachment.