AbstractWe analyzed two polymorphisms in genes encoding proteins of the dopamine system, the Val158Met polymorphism in the catechol‐O‐methyltransferase gene and the 120‐bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene for association with methamphetamine abuse. We used a case/control design with 416 methamphetamine abusing subjects and 435 normal controls. All subjects were Han Chinese from Taiwan. We found an excess of the high activity Val158 allele in the methamphetamine abuser group, consistent with several previous reports of association of this allele with drug abuse. The 120‐bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene itself did not show significant association with methamphetamine abuse. However, analysis of the 120‐bp VNTR polymorphism and the exon 3 VNTR in the dopamine D4 receptor as a haplotype showed significant association with methamphetamine abuse, which gave an empirical P value 0.0034 for a heterogeneity model. Moreover, there were significant interactive effects between polymorphisms in the catechol‐O‐methyltransferase and dopamine D4 genes. The evidence of interaction between COMT 158 Val/Met and DRD4 48‐bp VNTR polymorphisms (P = 0.0003, OR = 1.45, 95% CI: 1.148–1.77), and between COMT 158 Val/Met and DRD4 120 bp promoter polymorphisms (P = 0.01, OR = 1.10, 95% CI: 1.10–1.18) were significant but the latter was weak. We conclude that genetic variation in the dopamine system may encode an additive effect on risk of becoming a methamphetamine abuser. © 2004 Wiley‐Liss, Inc.