Cavities in proteins call 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 (SF6) 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 SF6 is straightforwardly detected by the F-19 chemical shift, line width, or longitudinal relaxation time measurements, which call be carried out at low SF6 concentration without interference from resonances of the protein. Most interestingly, the binding of SF6 gives rise to selective intermolecular H-1{F-19} heteronuclear Overhauser effects (HOEs). Molecular dynamics simulation and NMR spectrum modeling show that the experimental HOESY spectra are consistent with H-1{F-19} HOEs arising from SF6 in the cavity of LTP. SF6 is found to be an advantageous alternative to hyperpolarized Xe-129 and small organic Compounds for probing cavities in proteins by solution-state NMR.