The transport of digoxin was observed to be mediated by the multidrug resistance protein 1 (MDR1) gene product, P-glycoprotein and probably by organic anion transporting polypeptide 2 (OATP2). A total of 94 Taiwanese with serum creatinine values = 1.5 mg/dl who received low dose digoxin treatment (0.125 mg per day) were enrolled in this study. The record of co-administered P-glycoprotein inhibitors was reviewed for every patient. The most important single nucleotide polymorphisms of the MDR1 (C1236T, G2677T and C3435T) and OATP2 (G388A and T521C) genes were determined by the methods of polymerase chain reaction-restriction fragment length polymorphism. The 94 study subjects were divided into case group [N = 20 with adverse drug reaction (ADR), a trough serum digoxin = 2.5 ng/mL was observed within a one-year period subsequent to treatment] and control group (N = 74 without ADR). The results demonstrated that there was neither difference of MDR1 1236 C > T, 2677G > A,T and C3435C > T haplotypes nor difference of OATP2 388 G > A and 521 T > C haplotypes between the case and the control groups (P = 0.532~0.991). However, significant difference of the frequency for co-administration with P-glycoprotein inhibitors was observed (P = 0.004). In conclusion, for the patients with impaired renal function, digoxin ADR may be caused by P-glycoprotein inhibitor co-administration rather than by MDR1 and OATP2 polymorphisms.