The peroxide-initiated degradation of polypropylene in conventional screw elements of closely intermeshing twin-screw extruders is analyzed by means of a three-dimensional (3D) simulation approach. The 3D simulations of the reacting flow are implemented under the assumption of steady-state flow conditions, and scale-up considerations are addressed by simulating screw elements of two different size extruders. The effects of the initial peroxide concentration and reference mass throughputs on processing parameters are analyzed in terms of the specified extruder size. In this study, the scaled-up mass throughput is determined under the assumption of constant residence time. For the implemented processing conditions, the final values of the weigh-average molecular weight (Mw) and polidispersity index (PDI) for both the reference and scaled-up screw elements are similar when the flow rate is close to that corresponding to the maximum conveying capacity of the screw elements. For more restricted flow conditions, however, lower values of both the Mw and PDI are obtained for the larger screw element. Additionally, a previously proposed scale-up procedure from one-dimensional (1D) simulations is evaluated by means of a 3D simulation analysis. The results of this evaluation show a good agreement between the trend of the 3D and 1D simulation results.