Summary: Deuterated compounds are generally considered to possess very similar properties to their protonated analogues. Reversed phase liquid chromatography (RPLC) was used to measure thermodynamic interactions between deuterated and protonated n‐butyl polystyrenes and a C18 stationary phase. Significant differences in enthalpies and entropies of interaction were observed for deuterated and protonated n‐butyl polystyrenes. This is very important because many techniques, such as small‐angle neutron scattering and neutron reflectivity, assume that the interaction of these molecules are identical.