Background: Type II diabetes mellitus (T2DM) is increasing at an alarming rate in urban as well as rural parts of India. Change in life-style, dietary habits, aging, environmental factors contribute to developing this disorder, T2DM is a polygenic disorder which involves large number of genes interacting with each other and the environment to manifest itself phenotypically. Aims and Objectives: In the present study, we investigated the association of Vitamin D receptor (VDR) and Paraoxonase I (PON I) gene polymorphisms with T2DM patients among rural population in South western Maharashtra. Materials and Methods: The study groups included healthy non-diabetic control group (n = 120), non-obese diabetic group (n = 120), obese diabetic group (n = 120) from the same geographical region. The single nucleotide polymorphisms (SNPs) amongst these groups were studied using Polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) for VDR and PON I genes. Results and Conclusion: Amongst the studied genes VDR SNP rs1544410 [OR 0.24 (0.1-0.63); P 0.005] and Paraoxonase I SNP rs854560 (OR 0.47 (0.26-0.84); P 0.015) had a protective effect against T2DM for non-obese individuals. Whereas only VDR SNP rs1544410 [OR 0.025 (0.003-0.91); P 0.001] had a protective effect in case of obese individuals. The findings suggest greater gene-gene interaction and gene-environment interactions influence the phenotypic outcomes of genetic polymorphisms.