Background:  polymorphisms of the interleukin-1 (IL-1) gene family have been proposed as potential variants for different diseases including multiple sclerosis (MS). With respect to MS, IL-1 beta (−511 C/T; rs16944), IL-1 beta (+3954 C/T; rs1143634), IL-1 alpha (−889 C/T; rs1800587), IL-1 alpha (+4845 G/T; rs17561), and the variable number of tandem repeats in intron 2 of the IL-1 receptor antagonist (IL-1RN) gene polymorphisms have been studied in different ethnic groups, leading to conflicting results. Methods:  this study investigates the association between IL-1 genes and MS by means of 70 markers spanning the 1.1 Mb region where the IL-1 genes map and exploring both the linkage disequilibrium (LD) and the haplotype structure in a case–control design including 410 subjects (160 patients and 250 controls). Results:  from allelic/genotypic tests, significant association was found for several polymorphisms including the IL-1 beta (−511 C/T) variant (P-adjusted = 4.5 × 10−4) and some polymorphisms around the IL-1RN gene. The ‘block-step’ pattern obtained from both the LD map and pairwise analysis identifies four LD regions. Region 1 showed a significant association with MS for the global test (P