Appropriate decision making is an important brain function to maintain our lives. The Iowa gambling task (IGT) is a tool for decision making under ambiguity. The aims of this study were to evaluate the influence of serotonin transporter linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) polymorphisms and their interaction on IGT performance. One hundred fifty-nine normal subjects were involved in this study. All subjects performed the IGT and were genotyped for the triallelic 5-HTTLPR and DRD4 48 bp uVNTR polymorphisms. After controlling for gender, age, and impulsiveness, there were no main effects of 5-HTTLPR and DRD4 gene polymorphisms on total IGT score. However, there was a significant effect on the interaction between 5-HTTLPR and DRD4 on total IGT score. In the presence of the 5-HTTLPR S'S' (SS+SL(G)+L(G)L(G)), subjects with the DRD4 2R+ (2 repeat carrier) had higher total IGT score compared to those with the DRD4 2R-. In contrast, in the absence of the 5-HTTLPR S'S', subjects with the DRD4 2R- had higher total IGT score than those with the DRD4 2R+. When we divided IGT scores into the first and second half of trials, the 5-HTTLPRxDRD4 interaction effects were stronger in the second half block (decision under risk) than in the first half block (decision under ambiguity). In conclusion, the DRD4 genotypes might influence decision-making performance differently according to the background genotypes of 5-HTTLPR.