The aim of the present study was to investigate the nanoemulsion system for enhanced percutaneous penetration of domperi- done. Pseudoternary phase diagrams were constructed in order to optimize the surfactant, cosurfactant and surfactant: cosurfactant weight ratios (Smix). Nine nanoemulsion formulations were selected, characterized and their ex-vivo permeation studies using rat skin were per- formed. The nanoemulsion formulations had small droplet size (<90 nm), uniform size distribution (PI, < 0.2) and low viscosity (<160 mP). The results demonstrated that the droplet size and viscosity of nanoemulsion decreased following decrease in the concentration of polysorbate 20, whereas transdermal flux was increased. The optimized formulation NE-B1, which contained oleic acid (4 % w/w), polysorbate 20 (10 % w/w), diethylene glycol monoethyl ether (20 % w/w) and water (64 % w/w) showed significant increase (P < 0.01) in the transdermal flux (169.32 ± 8.33 � g.h -1 cm -2 ). The in vivo studies revealed a 3.5 fold increase in relative bioavailability through transdermal application of NE-B1 formulation compared to oral drug suspension. Moreover, the effective drug plasma concentration was maintained for 16 hour after the transdermal application indicated that the developed nanoemulsion systems could be a promising carrier for the transdermal delivery of domperidone for prolonged period. Microemulsions are quaternary systems composed of an oil phase, a water phase, surfactant frequently in combination with cosurfactant (1-3). These spontaneously formed systems possess specific physicochemical properties such as transparency, optical isotropy, low viscosity and thermodynamic stability. In stable mi- croemulsion, droplet diameter is usually within the range of 10-100 nm (100-1000 A°), and therefore these systems are also termed as nanoemulsions (NE) (4). Due to their unique physicochemical properties, NE offer advantages over traditional topical and trans- dermal drug delivery formulations. Many studies have shown that NE formulations possess improved transdermal and dermal delivery properties both in vitro (5-17), as well as in vivo (18-22). The high solubilizing capacity of NE enables them to increase the solubility of poorly water-soluble drugs. Both, increase in solute concentra- tion and the tendency of the drug to favor partitioning into the stra- tum corneum make NE a useful vehicle to enhance transdermal drug permeability (23). As demonstrated by a recent publication (18), the transdermal permeation rate of a lipophilic drug significantly increased from NE as compared to macroemulsions. In macroemulsions the free mobil- ity of the active material between the internal (disperse) phase to the external (continuous) phase within the structure of the formu- lated system is limited due to the strong interactions between the surfactants that form tight interfacial film. In NE, the co-surfactant lowers the interfacial tension of the surfactant film, resulting in a more flexible and dynamic layer (3,14). The drug in this energy- rich system can diffuse across the flexible interfacial surfactant film, a thermodynamic process that increases partitioning and diffu- sion into the stratum corneum. This article is intended to demonstrate the feasibility of new o/w NE system for transdermal delivery of domperidone. Domperi- done is a dopamine (D2 receptor) antagonist with predominant peripheral activity. It is clinically effective in conditions such as diabetic gastroparesis, chronic dyspepsia, pediatric vomiting, cancer chemotherapy induced nausea and emesis (24). Owing to its high portion of hepatic first pass metabolism (~85 %) (25), its low mo- lecular weight (426 Da), its moderate lipophilicity (Log P, 3.9) as