Introduction In the era of precision preventive medicine, susceptible genetic markers for oro‐/hypopharyngeal squamous cell carcinoma (OPSCC) have been investigated for genome‐wide associations. Materials and Methods A case–control study including 659 male head and neck squamous cell carcinoma (HNSCC) patients, including 331 oropharyngeal cancer, treated between March 1996 and December 2016 and 2400 normal controls was performed. A single‐nucleotide polymorphism (SNP) array was used to determine genetic loci that increase susceptibility to OPSCC. Results We analyzed the allele frequencies of 664,994 autosomal SNPs in 659 HNSCC cases; 7 SNPs scattered in loci of chromosomes 5, 7, 9, 11, and 19 were significant in genome‐wide association analysis (Pc < 1.0669 × 10−7). In OPSCCs (n = 331), two clustered regions in chromosomes 4 and 6 were significantly different from the controls. We successfully identified a missense alteration of the SNP region in alcohol dehydrogenase 1B (ADH1B) (https://genome.ucsc.edu; hg38); the top correlated locus was rs1229984 (p = 1 × 10−11). Adjusted for environmental exposure, including smoking, alcohol, and areca quid, a region in chromosome 12, related to alcohol metabolism, was found to independently increase the susceptibility to OPSCC. The ADH1B rs1229984 AA genotype had better overall survival compared to the AG and GG genotypes (p = 0.042) in OPSCC. The GG genotype in rs1229984 was significantly associated with a younger age of onset than other genotypes (p = 0.001 and <0.001, respectively) in OPSCC patients who consumed alcohol. Conclusion ADH1B was an important genetic locus that significantly correlated with the development of OPSCCs and patient survival. This is a large genome wide association study for head and neck squamous cell carcinoma (HNSCC) in areca‐quid endemic region. Germline genetic variations in oro‐/hypopharyngeal cancer different from other HNSCCs. Alcohol dehydrogenase 1B (ADH1B) single‐nucleotide polymorphism (SNP) important in the susceptibility of oro‐ and hypopharyngeal cancer.