In order to evaluate all the important limbs of the immune system in the same patient population with rheumatic fever (RF) and rheumatic heart disease (RHD) cellular and humoral immune parameters as well as the immunogenetic profile in 265 North Indian patients with RHD were evaluated. They were studied for class in HLA antigens and 165 of them were also evaluated for the class II (DR locus) antigen profile. Data obtained was compared with 400 and 134 healthy controls respectively of the same ethnicity. Humoral immune parameters (Serum immunoglobulins IgG, IgA; Serum complement fractions C3, C4, C3d; circulating immune complexes and B lymphocyte numbers) and cellular immune parameters (total leucocyte and lymphocyte counts; T lymphocyte sub-populations-CD4, CD8 counts; lymphocyte migration inhibition to an extracellular streptococcal antigen, streptolysin 'O') were studied in 23 patients with RF, 21 patients with "inactive" RHD and 20 normal controls. Patients of RHD were noted to have an increased frequency of DR3 (P < 0.001; Relative risk = 2.3) and a decreased frequency of DR2 (P < 0.001; Relative risk = 0.3) as compared to the controls. Patients of RF had evidence of an altered regulatory T cell function (Increased CD4/CD8 ratio) and decreased cell mediated immunity to streptolysin '0'. An increased humoral immune response (increased B cell counts, elevated serum IgG, circulating immune complexes and C3d) was noted in patients of RF as well as "inactive" RHD. An integrated pathogenetic model with immune response associated antigens of the DR locus influencing selection of cardiac cross-reactive antigens by the antigen processing macrophages, an altered regulatory T cell function with decreased suppressor T cell activity leading to an abnormal immune response is proposed to explain the pathogenesis of RF. © 1990 Dr. K C Chaudhuri Foundation.