The present work aimed to develop an experimental and computational study for optimizing the centrifugal molecular distillation process to split heavy petroleum fractions. On the basis of the balance equations and Langmuir-Knudsen equation, a mathematical model was proposed. The influence of the evaporator temperature (EVT), the feed flow rate (Q) and the interactions between them, on the overall distillate mass flow rate (D) and the distillate yield (%D) was analyzed. A full 2(2) factorial central plus star rotatable (alpha = +/-root 2) composite design was performed in the experimental range from 423.15 to 603.15K for EVT and from 1.473 to 4.418 kg . h(-1) for Q. The optimized conditions, using response surface methodology, established that the EVT must range from 540 to 600K and the Q from 1.5 to 3.5 kg . h(-1). The comparison of the experiment results with the predicted model results shows an acceptable qualitative agreement between the experiment and simulated data.