Oral and laryngeal cancer has a high incidence in the Basque Country (Spain), the main risk factors in this pathology being regular consumption of tobacco and alcohol. However, since not all the individuals exposed to these risk factors develop cancer, the individual genetic susceptibility should be investigated in this population. The aim of this study was to determine the distribution of alcohol dehydrogenase-1B polymorphism (Arg48His; rs1229984) in our region and analyze its association with the risk of oral and laryngeal squamous cell carcinoma. Samples from 87 patients with oral or laryngeal cancer and 242 healthy controls were analyzed. Multivariate logistic regression analysis showed that the combined Arg/His and His/His genotypes were associated with a reduced risk of head and neck squamous cell carcinoma (odds ratio: 0.203; 95% confidence interval: 0.052-0.796). In conclusion, the histidine allele was associated with a reduced risk of oral and laryngeal cancer in the Basque Country.