The removal of a Pharmaceutically Active Compound (PhAC) pool using a well referenced clay mineral from Wyoming (SWy-2) as a geosorbent was studied for a better understanding of the environmental fate. As expected, the selected material shows its particular adsorption properties to PhAC under different experimental conditions with two main features depending on the chemical nature of the emerging micro-pollutants. Cationic PhACs, for which the driving force for their adsorption results from electrostatic interaction via the exchange with the inorganic cations of the clay mineral, are almost completely removed for all studied experimental conditions where it appears that the S/L ratio plays a minor role and the only one limitation for their removal is the cation exchange capacity of the adsorbent. In contrast, anionic and neutral PhACs are adsorbed to the clay mineral surface (silanol groups on the sheet edges, inorganic cations…) through other interactional mechanisms involving ion–dipole, van der Waals interaction, leading to a competition of all organic molecules where their chemical nature (electric charge, hydrophobicity) may also play a role in their adsorption. While the adsorption of ketoprofen, naproxen, diclofenac and salicylic acid anionic PhACs slightly increases with the increase of the S/L ratio, the removal of the neutral and the other anionic PhACs (gemfibrozil and ibuprofen) seems to be independent of that ratio and is particularly enhanced. The efficiency of the removal for a global pool of PhACs even in low S/L ratio stresses the control of the selected natural minerals on the dynamics of PhACs in the environment.