To test the importance of the dopamine D2 receptor (DRD2) region in nicotine dependence, 150 smokers and 228 controls were genotyped for the . DRD2 C957T, -141delC and . ANKK1 TaqIA polymorphisms (rs6277, rs1799732 and rs1800497, respectively). The -141delC SNP did not show any association but both the C957T and . TaqIA SNPs showed association at the allele, genotype, haplotype and combined genotype levels. The 957C/. TaqI A1 haplotype was more than 3.5 times as likely to be associated with nicotine dependence compared with the 957T/. TaqI A1 haplotype (. P=. 0.003). Analysis of the combined genotypes of both SNPs revealed that individuals who were homozygous for the 957C-allele (CC) and had either one or two copies of the . TaqI A1-allele were 3.3 times as likely to have nicotine dependence compared to all other genotype combinations (. P=. 0.0003) and that these genotypes accounted for approximately 13% of the susceptibility to nicotine addiction in our population. Our findings suggest that the . DRD2 C957T polymorphism and the . ANKK1 TaqIA polymorphism are key contributors to the genetic susceptibility to nicotine dependence.