Interactions of drug molecules embedded within the pores of drug-delivery matrices significantly influence the drug-release rate and profile. In this Article, we used solid-state NMR experiments to inspect the interactions of indomethacin drug and tetrahydrofuran solvent molecules within mesoporous MIL-101 metal-organic framework materials. MIL-101 matrices were prepared using two types of linkers, terephthalic acid for MIL-101(Cr) and MIL-101(Fe), and amino-terephthalic acid for MIL-101(Al)-NH2 and MIL-101(Fe)-NH2. Loading MIL-101 matrices with indomethacin proved to be very efficient; the obtained delivery systems accommodated from 0.9 to 1.1 g of indomethacin per 1 g of MIL-101 material. NMR measurements showed that regardless of the type of the framework metal centers or the type of the organic linker indomethacin did not attach to the metal-organic framework. Interactions between indomethacin molecules themselves were also not detected. On the contrary, the smaller tetrahydrofuran solvent molecules did attach to the framework metallic trimeric units with hydrogen bonds. The bonds and the geometry of the porous system prevented the tetrahydrofuran molecules to be expelled from the MIL-101 matrix during drying. Information on interactions and proximities among neighboring nuclei was obtained by H-1 homonuclear correlation and H-1-C-13 heteronuclear correlation NMR measurements. Distance-dependent influence of paramagnetic chromium and iron centers was also exploited.