A variety of poly(ethylene oxide) (PEO)-based matrix tablets loaded with theophylline, ibuprofen or metoprolol tartrate was prepared via hot melt extrusion. The initial drug loading was varied from 10 to 60 %, the PEO polymer molecular weight from 300 to 7,000 kDa. The extrudates were characterized before and after exposure to phosphate buffer pH 7.4 at 37 °C using optical and scanning electron microscopy, X-ray diffraction analysis and drug release measurements. In the case of metoprolol tartrate, the resulting drug release rates monotonically increased with increasing initial drug loading, irrespective of the PEO grade. This can be attributed to an “increased porosity effect” upon drug leaching, resulting in less hindrance for subsequent drug release. However, in the case of theophylline and ibuprofen, also “limited drug solubility effects” played a role and were even dominant in 7,000 kDa PEO-based extrudates: Upon water penetration into the system, not all of the drug was dissolved. Dissolved and non-dissolved drug co-existed. Importantly, only dissolved drug is available for diffusion. Thus, increasing the initial drug content did not increase the concentration gradients of dissolved drug (and the absolute drug release rates in the absence of porosity effects), but increased the 100 % reference values. Interestingly, in 300 kDa PEO-based extrudates, “increased porosity effects” dominated for all drugs, and the relative release rates always increased with increasing drug loading. At 1,000 and 7,000 kDa, the resulting released rate increased or decreased with increasing drug loading, depending of the type of drug.