The aim of this study was to investigate the possible influence of a 3' untranslated region (3' UTR) polymorphism of the IL12B gene in susceptibility to Trypanosoma cruzi infection or in the development to cardiomyopathy in Chagas' disease (CD). We determined the IL12B 3' UTR genotypes in a sample of 200 seronegative individuals and 260 serologically positive patients (130 with Chagasic cardiomyopathy and 130 asymptomatic). All individuals are from a Colombian region where T. cruzi infection is endemic. Genotyping was performed by the PCR-restriction fragment length polymorphism (RFLP) method. The overall distribution of the IL12B 3' UTR alleles and genotypes in seronegative compared with seropositive individuals was not statistically significant. Interestingly, we found that the IL12B 3' UTR CC genotype was significantly increased among cardiomyopathic patients when compared to asymptomatic individuals (16% versus 5%; P=0.005; P(c)=0.015; OR=3.39; 95% CI 1.3-9.15). In addition, we observed that the IL12B 3' UTR C allele was present at significantly higher frequency in cardiomyopathic (33% versus 22%; P=0.008; P(c)=0.016; OR=1.69; 95% CI 1.12-2.55) as compared to asymptomatic. Our results suggest that IL12B 3' UTR gene polymorphisms may influence the susceptibility to develop Chagasic cardiomyopathy.