Leptin been mainly produced by adipose tissue and cancer cells is the most studied adipokine, amongst the several cytokines. Leptin is an antiapoptotic molecule and inducer of cancer stem cells as well as activates cell proliferation. Its oncogenic, mitogenic, proinflammatory and proangiogenic actions lead to its vital roles in tumourigenesis. Two common functional DNA polymorphisms in the genes of leptin G2548A (LEP) and leptin receptor A668G (LEPR) affect the amount of circulating cytokine-type hormone leptin with risk for development of oral squamous cell carcinoma (OSCC). The present study investigated whether these LEP and LEPR gene polymorphisms are affecting risk for OSCC by comparing the genotypes of patients with controls. A total of 306 OSCC and 228 controls participated in this study. We have determined the frequency of LEP (G2548A) and LEPR (A668G) gene polymorphisms in OSCC cases and controls by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The incidence of leptin gene G2548A homozygous mutant AA polymorphism was significantly increased in the OSCC patients (p = 0.002, odds ratio (OR) = 2.4, 95 % confidence interval (CI) = 1.37-4.22) when compared with controls, and leptin receptor A668G homozygous mutant GG polymorphism was significantly high in the OSCC patients as compared to controls (p = 0.000, OR = 3.8, 95 % CI = 1.98-7.62). The polymorphism of homozygous mutant allele A of leptin gene and G allele of leptin receptor may be associated with increased risk for OSCC. The observations showed regular increase of supporting role of leptin in OSCC. The present study showed an association of AA genotype and A allele of LEP G2548A as well as GG genotype and G allele of LEPR A668G polymorphisms with increased risk for OSCC in north Indian patients. Moreover, the combination of both the polymorphisms may be involved in susceptibility and progression of OSCC.