Chronic periodontitis (CP) is the common form of inflammatory oral disease. Matrix metalloproteinases (MMPs) play a pivotal role in the progression of CP by degrading gingival tissue and its remodelling. Here, we conducted a case-control study to investigate a possible association of single-nucleotide polymorphism of MMP genes and their interaction with CP in the Indian population. A total of 357 DNA samples of venous blood was isolated, of which 157 were identified as CP patients and 200 were healthy individuals. Genotyping of six MMP genes (MMP1, MMP3, MMP7, MMP8, MMP12 and MMP13) was done using polymerase chain reaction following Sanger's method of sequencing. Statistical analyses were performed by SPSS v16.0, R package (SNPassoc). Gene-gene interactions were evaluated by MDR 3.0.2. The frequency of 6A allele of MMP3 -11715A-6A gene polymorphisms (36%) and G allele of MMP8 +17G-C gene polymorphisms (34%) were higher in the CP population compared with the healthy population (19% and 24%, respectively). A significant association of T allele of MMP8 -799C-T gene promoter polymorphism was found with CP (OR = 2.95, 95%CI = 2.16 - 4.04, P < 0.0001). Genotypic frequency of MMP12 -82A-G polymorphism is associated with CP risk while its allelic distribution is not (OR = 1.32, 95%CI = 0.93 - 1.88, P = 0.129). Gene-gene interactions show the best cross validation consistency model, i.e. MMP1 -519A-G X MMP7 -181A-G X MMP8 -799C-T polymorphismswith a value of 9/10. This gene-gene interaction shows that the significant association of MMP8 -799C-T polymorphism with CP increased susceptibility. Allelic distribution of MMP8+17G-C and MMP3-11715A-6A polymorphisms revealed their protective role towards decreased risk of CP. MMP1 -519A-G and MMP7 -181A-G polymorphisms show combinatorial synergistic effect on CP risk.