Mesoporous silicas are currently widely studied carrier matrices in drug delivery applications. Surface functionalization of the silica is often employed in order to enhance the interaction between the drug and the support. However, in many cases the effectiveness of the introduced surface functions is much lower than what could be expected, and the release rate from surface functionalized silica is often not very different from that of the bare silica support, suggesting that the drug–support interactions are weaker than assumed under physiologically relevant conditions. We have therefore studied the adsorption of a model acidic drug, salicylic acid, to amino-functionalized mesoporous silica both from organic solvents, and from water as a function of pH, in order to rationalize these findings. It is shown that the nature of the organic solvent has a great influence on the loading degree, which however is more pronounced for the pristine silica materials due to absence of strong drug–support interactions. More importantly, the net effective surface charge of the adsorbent was found to control the adsorption process in water, and remaining silanols on the silica surface after functionalization have a marked influence on the drug–support interactions. The results can explain the relatively minor influence of amino groups on the release of acidic drugs reported in the literature, and gives a rational basis for optimization of support–drug interactions. The results are also of interest for optimization of drug immobilization and purification, as many medicinal and biologically active compounds are organic acids.