Risperidone (RIS) is a frequently used efficacious psychotropic drug. However, it prolongs the QTc interval and may cause fatal arrhythmia. Little is known on the determinants of this RIS side effect. RIS is metabolized by CYP2D6, and is subject to drug efflux by P-glycoprotein (P-gp) encoded by the ATP-binding cassette subfamily B member 1 (ABCB1) gene. P-gp removes both RIS and its metabolite 9-OH-RIS from cardiac tissue. To investigate the effect of RIS metabolism and ABCB1 gene polymorphisms on QTc, steady-state plasma RIS and 9-OH-RIS levels, and QTc were measured. CYP2D6, ABCB1 C3435T and G2677T/A genotypes were determined in 66 schizophrenia patients on RIS. QTc was significantly longer in patients with ABCB1 3435CT+3435 TT than in those with 3435CC (P=0.006). ABCB1 G2677T/A genotype did not affect QTc. Multiple regression analysis showed that C/T or T/T genotypes at the ABCB1 C3435T locus, lower weight, and older age prolonged QTc. In summary, the T allele of the ABCB1 C3435T genotype should be considered in future diagnostic development efforts for RIS-associated QT.