Significant effects of maghemite (γ-Fe 2 O 3 ) nanoparticles on the voltammetric behavior of carbon paste electrode for bio determination of dipyridamole (DIP) were studied. The electrochemical performance of maghemite NPs modified carbon paste electrode (MMCPE) was investigated (compared to unmodified and the other manufactured modified electrodes) and the mechanism was studied by using differential pulse voltammetry (DPV) and cyclic voltammetry (CV) techniques. Herein we utilized statistical based experimental design for simple optimization of effective parameters on the response of the electrode. Results indicate that MMCPE can remarkably enhance electrocatalytic activity toward the oxidation of dipyridamole (DIP) in Britton−Robinson buffer at pH 2.0. Under optimal conditions a detection limit of 5.0 × 10 −9 mol L −1 (2.5 ng mL −1 ) was obtained by DPV. The advantageous method was then tested for the simple, rapid and sensitive electrochemical determination of DIP in pharmaceutical formulations and human plasma as real samples.One of the most influential transition metal oxides in technological importance are iron oxides, specially magnetite, Fe 3 O 4 , and maghemite, γ-Fe 2 O 3 . At the nanoscale these materials have great characterizations and potential applications. They use as catalytic materials, wastewater treatment adsorbents, pigments, flocculants, coatings, gas sensors, ion exchangers, lubrication, magnetic recording devices, magnetic data storage devices, toners and inks for xerography, magnetic resonance imaging, electrochemical biosensors, medicine and biomedical purposes. [1][2][3][4][5][6] Determination of drugs in pharmaceutical, clinical and biological environments is necessary due to the control of drug quality, stability, metabolism and the study of pharmacokinetics including their toxicity. 7 Dipyridamole (DIP) is commonly used as a coronary vasodilator and antiplatelet drug that binds to plasma protein over 99%. α-acid glycoprotein (AGP) and albumin are responsible for the high protein binding of DIP in plasma. It has been reported that DIP and its analogs enhance the in vitro activity of antimetabolite anticancer drugs by reducing AGP binding. 8 DIP like as other Extra Pharmacopeia drugs, is officially listed in Martindale. Numerous determination methods of the anti-oxidant DIP have been reported such as HPLC, 7-13 spectrophotometry, 14-16 fluorimetry, [17][18][19] phosphorimetry, 19,20 and chemiluminescence. 5,21 voltammetric and polarographic methods 22-26 were performed recently due to the linear relation between the peak current and the DIP concentration while electroanalytical techniques are similar to the redox biological reactions. They are also simple, time and cost effective, without clean-up procedure, portable, selective and sensitive. 27 For detection of the trace amounts of biologically important compounds the electrochemical methods using chemically modified electrodes have been widely used as sensitive and selective analytical techniques. Uses of carbon paste electrodes (CPE...