SummaryThe chromatographic behavior of zwitterions in Ion-interaction chromatography (IIC) is, investigated theoretically for the first time. The modification of the stationary phase in the presence of Ion-interaction reagent (IIR), and adsorption competition bel',,veen test analytes and IIR for inner layer sites are shown theoretically to change the partition coefficient for zwitterions.Experimental results from the literature concerning retention behavior of zwitterions in IIC, were used to test the new thermodynamic theory. Very reasonable estimates of (i) AG ~ values for the IIR adsorption onto the stationary phase (ii) total ligancl concentration, and (iii) dipolar moments validate the present thermodynamic model for the I IC of zwilterionic analytes.Retention equations are compared to those which can be obtained, if the net charge of the analyte is zero, from the most important retention models in IIC. None of them is able to explain, even in a qualitative way the retention behavior of zwitterions in IICwhereas, the present model is quantitatively able to do this.