HNC comprises tumors in the oral cavity, pharynx and larynx. Pakistan falls into a high risk of HNC geographical zone. Oral cancer is one of the most prevalent malignancy worldwide, it is the second most prevalent cancer in Pakistan after lung carcinoma in men and breast carcinoma in women. Epidemiological studies have reported that various factors render increased risk for HNC which include smoking, alcohol consumption, intake of betel quid, chewing of tobacco, naswar, ingestion of fruit and vegetables in very low quantity, hereditary factors and family history, exposure to carcinogens, poor oral hygiene and Epstein–Barr virus. This study was aimed to investigate the association of HNC with demographic variables, oral health indicators and 7 SNPs of 5 interleukin gene in a case-control study design. This study was conducted in two phases. In phase I, epidemiological study was carried out and in phase II SNPs study was carried out. There were 276 cases which were pathologically confirmed patients with HNC, and among those 231 were selected for SNPs analysis, prospectively recruited from the IRNUM, Peshawar, Pakistan, from Nov. 2015 to Aug. 2016. The controls (n=275) were ethnically and linguistically matched subjects without any oral pathology. The clinical and pathological detail and data regarding demographic variables, risk factors, and oral health indicators were obtained and blood was also collected for SNPs analysis. Descriptive statistics and logistic regression modeling were employed to analyze the data. There were 276 cases and 275 controls. Majority of participants (cases and controls) belonged to Pashto ethnicity (90%), poor socioeconomic background (85%), rural origin (68%), and were illiterate (54%). There were statistically no differences among the cases and xi controls with respect to demographic attributes. In the present study patients were mostly presented with cancer of oral cavity (61%) or larynx (13%). Results shows that a high proportion of patients had poor oral hygiene (88%). The other oral health indicators were: no toothbrushing (65%), no use of dental floss (45%) and mouthwash (98%), periodontal diseases (65%), certain missing teeth (79%), and use of denture (13%). Smoking was more prevalent among the patients compared to the controls (25% vs. 12%; OR=2.53; 95%CI:1.60-4.00; p<0.0001). Similarly, a significantly higher number of patients used naswar (41% vs. 18%; OR=3.15; 95%CI:2.13-4.66; p<0.0001). A stepwise logistic regression was used to assess combined effect of independent variables which revealed that poor oral hygiene (OR=9.45, 95%CI: 5.95-15.01), material used of toothbrush (OR=5.01, 95%CI:2.20-11.37), no use of mouthwash (OR=4.76, 95%CI:1.46-15.48), and periodontal diseases (OR=5.04, 95%CI:3.18-8.01), were the significant predictors of oral cancer. It is pertinent to mention that demographic variables appeared not significant in multivariable analyses. It was further assessed that in absence of smoking and naswar use, the aforementioned four variables and no toothbrush use were significant risk factors for oral cancer. In the present study 231 cases (newly registered patients) and 219 controls were recruited for SNPs analysis in the selected genes. A significantly high number of cases had poor oral hygiene compared to controls (90.5% vs 23.7%) (p<0.01). Majority of cases never brush the teeth compared to controls (89.6% vs 49.3%). Furthermore, the frequency of missing teeth and the use of naswar were significantly high among cases compared to control (p<0.001). However, very less proportion of xii subjects were found to be smokers (p=0.58). Only 1.7% of cases contrasting to 0.9% controls used to chew paan (p=0.69). Similarly, 1.3% of used to drink alcohol compared to 0.5% of controls (p=0.62). The polymorphisms data showed that out of seven SNPs, oneSNP (IL10 rs1800896 T/C) was found to significantly associated with oral cancer. This study suggests that oral health indicators and polymorphism in IL10 rs1800896 T/C in combination with smoking confer an increased risk of oral cancer in Pakistani patients.