In this study, Response Surface Methodology (RSM) was used to model and optimize the electrospinning parameters to obtain poly(2-hydroxylethyl methacrylate) (pHEMA) nanofibers which is challenging in terms of evaluating the optimum conditions in nanofiber production. A second order (quadratic model) polynomial function was used for correlation between electrospinning parameters (flow rate, applied voltage, polymer/ethanol concentration) and average fiber diameter. An electrospinning set-up was used to fabricate nanofibers and scanning electron microscopy (SEM) was used to determine the morphology and the size of the nanofibers with diameter ranging from 211 nm to 1661 nm. Results concluded that the concentration of polymer solution played an important role in distribution of fiber diameter. Based on RSM, the optimum pHEMA fibers with 245 +/- 35 nm diameter were collected at 13 mu L/min flow rate, 12 kV applied voltage at an ethanol: pHEMA ratio of 1.76.