Cytokines are multifunctional glycoproteins that play a vital role in the tumor microenvironment and progression of breast cancer. Genetic polymorphisms may influence the immune responses restrained by pro- and anti-inflammatory cytokine expression in tumors. Hence, the present study evaluated the contribution of Interleukin (IL) 6 (rs1800797, rs1800796, and rs1800795) and IL18 (rs1946518, rs187238, and rs549908) genotypes and their haplotypes to the risk, progression of breast cancer in South Indian population. The polymorphisms of IL6 -597G > A, -572C > G & -174G > C, and IL18 -607C > A, -137G > C, 105A > T were genotyped through PCR-RFLP and As-PCR assays in the blood DNA of 600 subjects. We have performed haplotype, LD, univariate, multivariate logistic regression, and Kaplan-Meier analyses for the obtained data. The frequency of AA genotype & A-allele of IL6 -597G > A, and CC genotype & C-allele of IL6 -174G > C polymorphism was higher in breast cancer patients and was found to be significantly associated with late (advanced) stage, metastasis, etc. Further, IL18 -607C > A, -137G > C, and 105A > T polymorphisms were found to be associated with lobular carcinoma subtype, PgR -ve, and HER2 +ve breast cancer patients. In survival analysis, we have observed that the C-allele of IL6 -174G > C polymorphism to be significantly associated with 5 years of overall survival in breast cancer subjects. All SNPs of the IL6 and IL18 genes showed perfect LD; the G-C-C, A-G-G, and A-C-C haplotype combinations of IL6 gene conferred 2.09, 2.25, and 4.72 folds risk for breast cancer respectively. Hence, our results suggest the importance of genotypic and haplotype analysis of IL6 and IL18 gene variants in the progression and risk prediction of breast cancer.