Only a small fraction of the streptococcal pharyngitis progress to rheumatic carditis, which implies that environmental, host and microbial factors interact to cause an aberrant immune response against the antigens of the microorganism that cross-react with cardiac tissues. Although there are numerous studies and a general consensus on the relation between human leucocyte antigen (HLA) class II antigens and rheumatic heart disease (RHD), the details and the culprit antigens are still controversial. The study was undertaken to examine 100 patients with chronic RHD and 100 controls for HLA class I and class II antigens for differences in prevalence. All samples were typed at the HLA-DRB1/3/4/5 and DQB1 loci by the sequence-specific primer (PCR-SSP) method at low resolution. For HLA class I antigens, HLA-B13 frequency was marginally increased in patients with RHD compared to controls without reaching statistical significance. For class II antigens, RHD patients had higher frequencies for HLA-DRB1*01 (RHD 24%, controls 10%), DRB1*04 (RHD 35%, controls 26%), DRB1*07 (RHD 18%, controls 11%) and HLA-DQB1*02 (RHD 32%, controls 17%) without reaching statistical significance, and significantly lower frequencies for DRB1*13 (P-c < 0.003, OR: 5.69), DRB5* (P-c < 0.003, OR: 33) and DRB3* (P-c = 0.03, OR: 2.66) compared to controls. It was concluded that host, microbial and environmental factors collude to create acute rheumatic fever (RF) and chronic rheumatic valve disease. The HLA-DRB1*13, DRB5* and DRB3* were protective against the development of rheumatic valve damage.