In this work, the determination of sulfamethoxazole (SMX) and sulfamethizole (SMT) as important sulfa drugs by differential pulse voltammetry and chemometric resolution methods is proposed. Modified carbon paste electrode (CPE) with Fe doped ZnO (FeZnO) nanorods was used as an efficient electrochemical sensor. Operating conditions and influencing parameters (involving several chemical and instrumental parameters) were optimized with central composite rotatable design (CCRD) and response surface methodology (RSM). To determine SMX and SMT with a high degree of overlapping, second-order electrochemical data was generated by changing the pulse height as an instrumental parameter. Under the optimized conditions, the dynamic range for SMX and SMT were from 2.0 to 160.0 and 2.5 to 170.0 mu M and it was found that the detection limits were 30.0 and 25.0 nM, respectively. The modified electrode showed an improvement in anodic oxidation activity of SMX and SMT as well as an obvious enhancement in the current response compared with the bare CPE in phosphate buffer solution. Also, the modified electrode shows good sensitivity, selectivity and stability. The proposed method was applied for simultaneous determination of SMX and SMT in spiked human serum and urine samples. (C) 2014 Elsevier B.V. All rights reserved.