Context: Dopamine receptor-mediated pathways play critical roles in the mechanism of addiction. However, associations of the D 2 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 �� 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 �� 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.