Incomplete drug release from mesoporous silica systems has been observed in several studies. This work aims to increase the understanding of this phenomenon by investigating the mechanism of drug-silica interactions and adsorption behavior from supersaturated aqueous solutions of two similar drug molecules with different hydrogen bonding capabilities. Drug-silica interactions between indomethacin or its methyl ester and SBA-15 were investigated using spectroscopic techniques (infrared, fluorescence and X-ray photoelectron) and adsorption experiments. The results demonstrate that the predominant mechanism of interaction of both drugs with silica is hydrogen bonding between drug acceptor carbonyl groups with donor groups on the silica surface. The presence of a drug hydrogen bond donor group did not enhance drug adsorption. No evidence was obtained for drug adsorption through nonspecific hydrophobic interactions. Drug adsorption onto the silica surface was investigated under supersaturating conditions through the generation of adsorption isotherms. Similar adsorption isotherms were observed for each compound when the concentration scale was normalized to the drug amorphous solubility. In other words, the equilibrium between the drug adsorbed on the silica surface and free drug in solution was related to the drug activity in solution. The high tendency of the drug to adsorb when the solution is supersaturated was, in turn, found to limit the extent of drug release during dissolution under nonsink conditions. Thus, adsorption provides an explanation for incomplete drug release.