This report presents a modified saturation transfer difference experiment for protein-ligand binding studies. A heteronuclear saturation transfer difference (HSTD) is suggested, where in a hetero atom, such as carbon is utilized for monitoring the binding instead of proton. This method is free from some of the problems associated with proton STD experiment, such as lack of sufficient number of protons at the binding site or crowding of spectra due to smaller chemical shift dispersion. The present method has been demonstrated on three systems namely caffeine-HSA, salicylic acid-HSA and glucose-lysozyme, illustrating the utility of the method. (c) 2006 Elsevier B.V. All rights reserved.