Objectives: Head and neck cancer (HNC) is one of the most common cancers. Most exogenous HNC is head and neck squamous cell carcinomas. Scientists are striving to develop diagnostic tests that will allow the prognosis of HNC. The aim of the study was to determine the risk of HNC. The research concerned changes caused by polymorphisms in genes encoding proteins responsible for the metabolism of xenobiotics. Material and Methods: In group of 280 patients with HNC, the occurrence of polymorphic variants in NAT1(rs72554606), NAT2(rs1799930), CYP1A(rs1799814), CYP2D(rs3892097) were studied with TaqMan technique. The control group consisted of 260 cancer free people. The TNM scale was analyzed. Gene interactions of genotyped polymorphisms were investigated. The effects of smoking and alcohol consumption on HNC were assessed. Results: The results indicated an increased risk of HNC in NAT1 polymorphisms in the GC genotype (OR = 1.772, 95% CI: 1.184–2.651, p = 0.005) and NAT2 polymorphism in the GA genotype (OR = 1.506, 95% CI: 1.023–2.216, p = 0.037). The protective phenomenon in the CYP1A polymorphism the GT genotype (OR = 0.587, 95% CI: 0.381–0.903, p = 0.015) and the TT genotype (OR = 0.268, 95% CI: 0.159–0.452, p = 0.001). The coexistence of GA-GC polymorphisms (OR = 2.687, 95% CI: 1.387–5.205, p = 0.003) in NAT2-NAT1 genes increases the risk of HNC. Risk-reducing effect in the polymorphism GG-GT (OR = 0.340, 95% CI: 0.149–0.800, p = 0.011), GG-TT (OR = 0.077, 95% CI: 0.028–0.215, p < 0.0001), GA-TT (OR = 0.250, 95% CI: 0.100–0.622, p = 0.002), AA-GT (OR = 0.276, 95% CI: 0.112–0.676, p = 0.002) in NAT2-CYP1A genes. In the CYP2D-CYP1A genes in the polymorphisms CT-CC (OR = 0.338, 95% CI: 0.132–0.870, p = 0.020), TT-GG (OR = 0.100, 95% CI: 0.027–0.359, p = 0.001), TT-GC (OR = 0.190, 95% CI: 0.072–0.502, p = 0.0004), TT-CC (OR = 0.305, 95% CI: 0.107–0.868, p = 0.024). Correlation was noted between cigarette smoking and HNC (OR = 7.297, 95% CI: 4.989–10.674, p < 0.0001) and consuming alcohol (OR = 1.572, 95% CI: 1.003–2.464, p = 0.047). Conclusions: The CYP1A polymorphism shows a protective association with HNC. On the other hand, NAT2, NAT1 polymorphism influence the susceptibility to developing HNC. The coexistence of the NAT2-NAT1 genotypes increases the risk of HNC. In contrast, NAT1-CYP1A and CYP1A-CYP2D reduce this risk. Smoking and alcohol consumption increase the incidence of HNC. Int J Occup Med Environ Health. 2023;36(6):812–24