The aim of this study was to evaluate the pharmacokinetics of paclitaxel-loaded nanosponges (PLN) in rats. The study also evaluates the intrinsic effect of the dosage form on the improvement of paclitaxel oral bioavailability. Paclitaxel-loaded nanosponges were prepared and characterized in terms of size distribution, drug solubilization, and the kinetics of paclitaxel sedimentation. Taxol((R)) and paclitaxel-loaded nanosponges were administered orally to rats. The plasma concentration of paclitaxel was determined using liquid chromatography. The average size of PLN was 350 +/- 25 nm. The drug payload of paclitaxel was 500 +/- 0.27 mg/g of lyophilized powder. The encapsulation efficiency was 99.1 +/- 1.0%, and 1.7 +/- 0.2% of paclitaxel was crystallized after 48 h. The relative oral bioavailability of paclitaxel-loaded nanosponges was 256. After oral administration of paclitaxel-loaded PLN, the area under the plasma concentration time curve was significantly increased ( approximately 3-fold) in comparison to the control group (p < 0.05). The results indicated that PLN provided a promising new formulation to enhance the oral bioavailability of paclitaxel while avoiding the use of cremophore El: Ethanol in Taxol((R)).