In this study, response surface methodology based on face center composite - 1/2 factorial fraction design (FCCD) of experiments was employed to optimize the batch transesterification process of waste cooking oil as one of the most abundant and readily available domestic wastes with methanol using immobilized Candida antarctica lipase (Novozym435) to maximize the production of high-purity biodiesel. Statistically significant second-order quadratic model equations (p < 0.0001) were elucidated through multiple regression analysis to describe the interrelationships between response of interest (biodiesel yield wt% and % conversion, i.e. the transesterification efficiency) and five independent variables (methanol:oil molar ratio, enzyme concentration wt%, reaction temperature degrees C, reaction time h, and mixing rate rpm). The statistical significance of the effect of these variables (factors) and their interactions on the transesterification efficiency was evaluated and the validity of the predicted models was confirmed. The optimum operating conditions were found to be: 3.63:1 M:O, 8.94 wt% Novozym435, 45.23 degrees C, 2.76 h, and 535.84 rpm. This produced 97 wt% biodiesel yield with % conversion of approximate to 91.79%. An overall acceptable agreement was achieved between the produced biodiesel fuel properties at the aforementioned optimal operating conditions and the Egyptian petrodiesel and international biodiesel standards.