Cavities in proteins can be studied experimentally by using some detectable atoms, such as xenon, or molecules which act as reporter, such as a spy. The interest of sulfur hexafluoride (SF(6)) for probing hydrophobic cavities by solution-state NMR is investigated. The wheat nonspecific lipid transfer protein (LTP) was selected as a model system for this purpose. The binding of SF(6) is straightforwardly detected by the (19)F chemical shift, line width, or longitudinal relaxation time measurements, which can be carried out at low SF(6) concentration without interference from resonances of the protein. Most interestingly, the binding of SF(6) gives rise to selective intermolecular (1)H{(19)F} heteronuclear Overhauser effects (HOEs). Molecular dynamics simulation and NMR spectrum modeling show that the experimental HOESY spectra are consistent with (1)H{(19)F} HOEs arising from SF(6) in the cavity of LTP. SF(6) is found to be an advantageous alternative to hyperpolarized (129)Xe and small organic compounds for probing cavities in proteins by solution-state NMR.