The interaction of diclofenac sodium salt (DCFNa) and two cyclodextrins, β-cyclodextrin (βCD) and 2-hydroxypropyl-β-cyclodextrin (HPβCD), studied in D2O solution with different NMR techniques (1H, 13C NMR, ROESY experiments, NMR titrations), shows the existence of multiple equilibria involving 1:1 and 2:1 guest–host complexes.