Three different extruders (the Alexanderwerk gravity feed roll extruder, the Gabler axial, single-screw extruder, and the NICA radial-screw extruder) were compared for their suitability for different placebo formulations and for fenoldopam pellets. A fourth extruder, the experimental ram extruder, was also included in some of the comparisons. Evaluation of the extrusion behavior of the three extruders showed differences as well as similarities among them, depending on the composition of the formulation. Although the NICA and Alexanderwerk units extruded all formulations successfully, the Gabler extruder failed to do so at a content of > 60% of soluble ingredients, such as lactose or mannitol. The extrudate surface improved for all extruders with an increase in water content of formulations, but was generally smoother for the Gabler than for the NICA or the Alexanderwerk units. A formulation with colloidal Avicel as spheronization aid showed an identical extrusion behavior for all of the investigated extruders. Of the three extruders, the Gabler unit showed the highest heat generation during extrusion, especially when extruding formulations with a low water content or high contents of soluble excipients. However, when the loss of water during extrusion or spheronization for various formulations was compared, only a two-way ANOVA test on the differences between the water content after extrusion and after spheronization showed a statistically significant difference between the Alexanderwerk or NICA and the Gabler extruder. The two-way ANOVA also proved that this difference is significant only for some formulations, e.g., lactose + Avicel PH 101 formulations, but not for Avicel PH 101 formulations.