The present work aims to characterize the nature and intensity of the specific and non-specific solute-solvent interactions responsible for the different solvating behaviour Of "CO2-expanded ethanol" and "CO2-expanded acetone" towards acetaminophen, an analgesic drug commercially known as paracetamol. The intermolecular interactions between acetarninophen and solvent molecules involved in these expanded media and its sensitivity to solvent composition changes, have been analyzed by high-pressure IR spectroscopy, LSER analysis, and theoretical ab initio calculations performed with acetaminophen-(ethanol)(n) and acetaminophen-(acetone), complexes. It comes out that the distinct perturbation experienced by the cybotactic region of acetaminophen in "CO2-expanded ethanol" and "CO2-expanded acetone" when CO2 content increases is basically a consequence of the higher sensitivity to solvent composition changes of the dipole-dipole interactions, established between the acetaminophen carbonyl group and acetone solvent molecules, in relation to that of the hydrogen bond interactions existing between this group and ethanol solvent molecules. (c) 2005 Elsevier B.V. All rights reserved.