To evaluate the HLA class I and II profiles of a large group of patients with Chagas' disease, 176 patients presenting with pure cardiomyopathy with heart failure (N = 60), cardiomyopathy without heart failure (N = 18), pure digestive tract manifestations (N = 25), cardiac plus digestive disease (N = 40), and asymptomatic patients with positive serology for chronic Trypanosoma cruzi infection (N = 33) were studied. A total of 448 normal individuals were also studied in parallel. HLA class I and II specificities were determined using serology and oligonucleotide analysis. HLA-A30 antigen was overrepresented in the total group and in the subgroups presenting with the pure cardiac (with or without heart failure) or digestive form, conferring similar relative risks and etiologic fractions on all these presentation forms. Serologic HLA class II analysis showed that HLA-DQ1 conferred susceptibility to, while HLA-DQ7 antigen conferred protection against the development of the disease in the total group of patients. Oligonucleotide typing did not confirm the HLA class II associations obtained by serology, but showed that HLA-DQB1*06 alleles were underrepresented in the total group and in the subgroups presenting with pure digestive or cardiac disease, conferring closely similar relative risks and preventive fractions. Although asymptomatic patients showed a tendency to increased HLA-A30, they presented a significant increase of HLA-DQB1*0302 specificity. In conclusion, HLA-A30 antigen conferred susceptibility to, while HLA-DQB1*06 specificity conferred protection against, the development of the disease, regardless of the form of presentation, ie, cardiac or digestive tract disease.