OBJECTIVES. Clarifying the association between bipolar I and bipolar II disorders at the genetic level is essential for improving our understanding of them. In this study, we evaluated the hypothesis that the dopaminergic polymorphisms are risk factors for bipolar disorders. We examined the association between the catechol-O-methyltransferase (COMT) Val158Met and dopamine D3 receptor (DRD3) Ser9Gly polymorphisms and bipolar I and II disorders, as well as possible interactions between these genes. METHODS. Seven hundred and eleven participants were recruited: 205 with bipolar I, 270 with bipolar II, and 236 healthy controls. The genotypes of the COMT Val158Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. RESULTS. Logistic regression analyses showed a statistically significant main effect for the Met/Met genotype of the COMT Val158Met polymorphism (P=0.032) and a significant interaction effect for the Met/Met genotype of the COMT Val158Met and Ser/Ser genotypes of the DRD3 Ser9Gly polymorphism (P=0.001) predicted bipolar I patients. However, there was no association between the COMT Val158Met or DRD3 Ser9Gly and bipolar II. CONCLUSIONS. We provide initial evidence that the COMT Val158Met and DRD3 Ser9Gly genotypes interact in bipolar I and bipolar II disorders and that bipolar I and bipolar II are genetically distinct.