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Among the various candidate genes predisposing for cardiovascular diseases, HLA-DRB1* and IL-1β +3953C/T alleles have been implicated repeatedly. To test these in South India, we carried out a case control study of 323 Coronary Artery Disease (CAD) patients, 56 Rheumatic Heart Disease (RHD) patients and 254 endemic controls. The polymorphisms were studied by PCR – SSP and ARMS-PCR methods and results analyzed for various clinical and demographic parameters. In CAD, HLA-DRB1*14 allele showed significant predisposition (OR: 2.19; 95% CI: 1.04–4.58; p value = 0.023), particularly in male patients (OR: 4.07; 95% CI: 1.20–13.81; p value = 0.01) and further in males with Triple Vessel Disease (OR: 5.49; 95% CI: 1.45–20.60; p value = 0.007). On the other hand, HLA-DRB1*15 predisposed for RHD (OR: 3.56; 95% CI: 1.87–6.78; p value = 0.001) in both the genders. Population stratification showed this higher risk association in Vanniyar caste (OR: 5.00; 95% CI: 1.27–19.59; p value = 0.022). Among the IL1-β +3953C/T polymorphism, the ancestral allele ‘C’ showed a significant high risk association with CAD (OR: 1.83; 95% CI: 1.24–2.70; p value = 0.001), particularly in Mudaliar (OR: 6.07; 95% CI: 1.77–20.74; p value = 0.003; AF = 0.7) and Vanniyar castes (OR: 3.67; 95% CI: 0.92–14.57; p value = 0.05; AF = 0.660). Two different cardiac ailments studied, RHD & CAD thus showed varied associations in this South Indian cohorts. RHD having an infectious aetiology shared a HLA-DRB1*15 high risk association, while HLA-DRB1*14 and IL-1β +3953C predisposed for CAD, an inflammatory disorder, reiterating the diverse genetic predisposition of the two cardiac ailments studied.