Though it is known that the immune system exerts some influence on the resistance against T. cruzi infection its precise role in this process is not well-understood. Some IL-1B alleles and haplotypes have been associated with susceptibility to inflammatory, autoimmune and infectious diseases. The objective of this study was to determine and compare the distribution of IL-1B and IL-1 receptor antagonist (IL-1RN) polymorphisms among T. cruzi seropositive patients, patients with idiopathic dilated cardiomyopathy (IDC) and healthy individuals. We studied 86 individuals seropositive for T. cruzi (58 patients with chronic chagasic cardiomyopathy (CCC) and 28 asymptomatics), 50 seronegative individuals with IDC and 109 healthy individuals. IL-1B-511, IL-1F10.3 IL-1RN.4, IL-1RN 6/1, and IL-1RN 6/2 polymorphisms were analyzed using real-time PCR allelic discrimination technology. Infected patients presented an increased frequency of the CC genotype of the IL-1RN.4 polymorphism when compared to IDC (pC = 0.028; OR = 11.46). The C allele of this polymorphism was found increased in CCC when compared with IDC (pC = 0.036; OR = 0.5) and with controls (pC = 0.035; OR = 1.87). CC genotype of IL-1RN.4 polymorphism was increased in patients with CCC when compared to IDC (pC = 0.0018; OR = 16.74) and healthy individuals (pC = 0.011; OR = 3.6). There is an evident association between the IL1RN.4 polymorphism, T. cruzi infection and CCC development.