Context Dopamine receptor–mediated pathways play critical roles in the mechanism of addiction. However, associations of the D2 dopamine receptor gene (DRD2) with substance abuse are controversial.Objective To determine whether susceptibility sites resided at DRD2.Design Haplotype-based case-control analysis of 2 distinct populations using 10 single nucleotide polymorphisms (SNPs) with heroin dependence.Setting Universities of Mainz and Bonn, Germany, and 3 local hospitals in southwestern China.Patients Cases and control subjects recruited from China (486 cases, 313 controls) and Germany (471 cases, 192 controls).Interventions Genotyping for 10 SNPs by 5'-exonuclease fluorescence assays. The D' value of linkage disequilibrium and haplotypes were generated by the expectation-maximization algorithm.Main Outcome Measures Genotype, allele, and haplotype frequencies were compared between cases and controls by 2 tests constructed for each population. An additional 32 SNPs randomly distributed in the genome were genotyped for detecting population admixture in the 2 populations.Results A haplotype block of 25.8 kilobases (kb) was defined by 8 SNPs extending from SNP3 (TaqIB) at the 5' end to SNP10 site (TaqIA) located 10 kb distal to the 3' end of the gene. Within this block, specific haplotype cluster A (carrying TaqIB1 allele) was associated with a high risk of heroin dependence in Chinese patients (P = 1.425 x 10–22; odds ratio, 52.80; 95% confidence interval, 7.290-382.5 for 8-SNP analysis). A putative recombination "hot spot" was found near SNP6 (intron 6 ins/del G), creating 2 new daughter haplotypes that were associated with a lower risk of heroin dependence in Germans (P = 1.94 x 10–11 for 8-SNP analysis). There was no evidence of population stratification in either population.Conclusions These results strongly support a role of DRD2 as a susceptibility gene with heroin dependence in Chinese patients and was associated with low risk of heroin dependence in Germans.