Hypertrophic cardiomyopathy is characterized by massive ventricular hypertrophy, reduced diastolic function, and excessive ventricular contraction. The human leukocyte antigens HLA-A, HLA-B, and HLA-DR were studied in 14 hypertrophic cardiomyopathy patients with left ventricular obstruction from South India. They were compared with 81 normal age- and sex-matched individuals from the same ethnic background. The human leucocyte antigens were identified using the standard serological assay with a longer incubation for DR antigens. The odds ratio, frequency, chi-squared value, p-value, etiological fraction, preventive fraction, and haplotype frequency estimates were calculated. The HLA-B51 and HLA-DR2 levels were significantly increased in hypertrophic cardiomyopathy patients compared to controls, whereas HLA-A19, HLA-B7, and HLA-DR4 were decreased when compared to the controls. It was noticed that haplotype B51-DR2-DQ3 was significantly associated with hypertrophic cardiomyopathy patients from South India. Hypertrophic cardiomyopathy may be associated with genes in the human leukocyte antigen region, and immunogenetic factors linked to human leukocyte antigens appear to play a major role in the pathogenesis.