Environmental factors such as stress influence both the predisposition to and development of alcoholism, as well as have significant implications for alcoholism relapse. One predominant biological response to acute stress is the release of norepinephrine, which activates the peripheral stress response and also the hypothalamic–pituitary–adrenal axis. We aimed to examine the role of two genes of the adrenergic system (SLC6A2 and ADRA2A) in alcoholism by genotyping 21 SNPs in 785 adult alcohol-dependent patients and 1237 controls. Two single nucleotide polymorphisms (SNP) (rs36020 and rs36029) in SLC6A2 were significantly associated with alcoholism [false discovery rate corrected P-value (FDR) P = 0.007]. Two SNPs in ADRA2A (rs521674 and rs602618) were associated with a positive family history of alcoholism (FDR P ≤ 0.05). A combined SNP-set analysis was also carried out to determine the risk of harbouring multiple alcohol risk alleles across SLC6A2 and ADRA2A. Logistic regression analysis revealed that an increase in the number of alcohol risk alleles increased the risk for alcoholism (P = 0.000567, odds ratio = 1.75, 95% confidence interval 1.26–2.44). A three-SNP haplotype consisting of rs187715, rs36020 and rs40147 alleles, AGC, was also found, which was significantly over-represented in cases compared with controls (61% versus 56%). We therefore demonstrate an association of SLC6A2 and ADRA2A with adult alcoholism. These data confirm the relevance of the adrenergic stress system when considering genetic predisposition to alcohol dependence and suggest that SLC6A2 and ADRA2A should be studied in additional alcohol-dependent cohorts.