In this study, the adsorption behavior of pyridine derivatives, i.e., 2-aminopyridine and 2,2'-bipyridyl, onto sepiolite, a natural clay mineral, has been investigated by bottle adsorption and IR spectroscopic techniques. The results indicate that 2-aminopyridine and 2,2'-bipyridyl molecules adsorb onto sepiolite through hydrogen bonding of the amino groups to the water molecules in the octahedral sheet and to the surface hydroxyls (Si-OH) in the tetrahedral sheet. These findings reveal that pyridine molecules not only adsorb onto the external surface of sepiolite but are also incorporated in its channels and tunnels with adsorption taking place at corners and/or edges, depending on the position of water molecules. A structural model is proposed to account for the orientation of pyridine derivatives in the sepiolite matrix.