Hot-melt extrusion has attracted considerable interest within the pharmaceutical industry. However, there remains some uncertainty as to how to characterise the physical structure of the extruded systems, particularly in terms of identifying the nature of the drug dispersion within the polymer. The aim of the study was to develop a combined thermal, imaging and spectroscopic approach for the identification and characterisation of the drug and polymer structure. Solid dispersions containing 10% and 20% paracetamol in EUDRAGIT® E were prepared by hot-melt extrusion into elongated strands. Differential scanning calorimetry (DSC) run at scanning rates up to 100 °C/min, modulated temperature DSC, microthermal analysis (µ-TA) and Attenuated Reflection Fourier Transform IR (ATR-FTIR) were used to characterise the systems. It was noted that the glass transition of the dispersions were considerably lower than the polymer alone, indicating dispersion of the drug in the polymer on a molecular basis. However, thermal and spectroscopic evidence was also obtained for the presence of crystalline drug at the 10% and 20% loadings, indicating that the drug was present in two physical forms simultaneously. Furthermore, both ATR-FTIR and microthermal analysis indicated that the drug crystals were preferentially located in the centre, rather than on the surface, of the extrudate. The study has indicated that the dispersion of the drug in the polymer may be complex in terms of both physical form and spatial distribution, with potential ramifications for stability and dissolution kinetics. In addition, the investigation has indicated that the combined approach outlined here is highly appropriate, as no single technique may yield all the required information.