BACKGROUND Although hypersensitivity reactions following intake of alcoholic drinks are common in Caucasians, the underlying mechanisms and clinical significance are not known. In contrast, in Asians, alcohol-induced asthma and flushing have been shown to be because of a single nucleotide polymorphism (SNP), the acetaldehyde dehydrogenase 2 (ALDH2) 487lys, causing decreased acetaldehyde (the metabolite of ethanol) metabolism and high levels of histamine. However, the ALDH2 487lys is absent in Caucasians. OBJECTIVE To investigate the genetic determinants of self-reported alcohol-induced hypersensitivity reactions in Caucasians. METHODS The study included two population-based studies of 1216 and 6784 adults living in Copenhagen. Assessment of alcohol consumption and hypersensitivity reactions (in a subgroup) was performed by a questionnaire and was related to common SNPs of genes encoding alcohol dehydrogenases (ADHs) and ALDHs. RESULTS In both populations, alcohol drinkers with a genetically determined fast metabolism of ethanol (the A allele of the ADH1b rs1229984) had an increased risk of alcohol-induced hypersensitivity reactions (odds ratio AA/AG vs. GG in combined populations: 1.82, 95% CI 1.04-3.17). In both populations, a common SNP encoding ALDH1b1 (rs2228093) was found to be significantly associated with alcohol-induced hypersensitivity (odds ratio TT vs. CC in combined populations: 2.53, 95% CI 1.31-4.90). CONCLUSIONS Our data support that alcohol sensitivity in Caucasians is genetically determined and suggest that a histamine-releasing effect of acetaldehyde represents a plausible biological mechanism. Furthermore, we present the first report of a clinically significant SNP within the acetaldehyde-metabolizing system in a Caucasian population.