The reactive extrusion of thermoplastic polyurethane in a corotating twin-screw extruder was investigated. The polyurethane system consisted of a mixture of 2,4-diphenylmethane diisocyanate (2,4-MDI) and 4,4-MDI, methyl-propane-diol and a polyester polyol. An engineering extrusion model was designed and compared with experimental results. In this validation study the catalyst level, throughput, rotation speed and the barrel wall temperature was varied. A comparison of the experiments with the model showed that the model captured the polyurethane extrusion fairly well. Furthermore, the effect of the depolymerization reaction on the polyurethanes extrusion was investigated. It was found that the extruder operation is gravely affected by the depolymerization reaction: the depolymerization reaction limits the maximal obtainable conversion, stabilizes the extruder operation, and causes undesired post-extrusion curing of the polyurethane.