Killer cell immunoglobulin-like receptors (KIR) are involved in regulating natural killer cell activation through recognition of their human leukocyte antigen (HLA) class I ligands. We conducted a case-control study with 169 oral squamous cell carcinoma (OSCC) patients and 177 healthy participants to study the genomic diversity of KIR and HLA loci and KIR gene expression in context of family history of cancer (FHC) in OSCC. Polymerase chain reaction (PCR) sequence-specific priming approach was used to type 16 KIR genes in individuals. SSP-real-time PCR was used for HLA class I ligand genotyping and real-time quantitative reverse transcriptase PCR was used to determine the expression of KIR gene. KIR2DL1(+)-HLA-C2(+) genotype was higher and positively associated with OSCC. Notably, all KIR2DL1(+)-HLA-C2(+) genotypes occurred exclusively in patients with FHC, showing a strong positive association of KIR2DL1(+)-HLA-C2(+) genotype with FHC. In addition, all younger age group patients (<55 years) with FHC were positive for KIR2DL1(+)-HLA-C2(+) genotype suggesting association of the genotype with early onset of disease. RNA transcript abundance of inhibitory KIR2DL1 in FHC patients, particularly of lower age groups (<45 and 45-54 years), supports the contention. Further, KIR2DL3(+)-HLA-C(+) genotype was negatively associated with OSCC. Our findings suggest KIR2DL1(+)-HLA-C2(+) genotype as heritable risk factor in OSCC predisposing to OSCC at younger age. Interestingly, KIR2DL3(+)-HLA-C(+) genotype was seen to be protective in OSCC. This study may be useful towards cancer surveillance and early detection of oral cancer in patients with FHC.