The association of the A1 allele of the D2 dopamine receptor gene with alcoholism was examined by comparing 32 unrelated white alcoholics with 25 unrelated white controls and by analysis of 17 nuclear families in multigenerational pedigrees of alcoholics in whom the A1 allele was segregating. All subjects had structured psychiatric interviews. Clinical assessment and genotyping were carried out independently. Thirteen (41%) of the 32 alcoholics carried the A1 allele compared with three (12%) of the 25 controls. The association with the A1 allele was significant when controls were compared with a subset of 10 alcoholics with severe medical problems (60% vs 12%), but not less severe cases. However, regardless of clinical severity or subtype, there was no evidence of linkage or cosegregation of the A1 allele and increased susceptibility to alcoholism in informative pedigrees. The possible association in the general population without linkage in families may be explained either by chance variation in our small samples or a modifying effect of the A1 allele that increases severity. Further study of the role of the D2 receptor gene in alcoholism is warranted.