The process performance of the separation and purification of proteins by ion-exchange simulated moving bed (IE-SMB) can be improved when a step-wise salt concentration is formed in the SMB unit, called salt gradient IE-SMB. In this paper, a gradient SMB model is used to analyze the performance of the salt gradient IE-SMB process, based on literature data for linear adsorption of proteins. Some strategies are discussed for the selection of salt gradient in IE-SMB chromatography for proteins effective separation. Three configurations of the gradient SMB process, open loop, closed loop, and closed loop with a holding vessel are compared. When running a gradient SMB with closed loop configuration, a holding vessel with a given volume is added to the system to mix online the desorbent with the recycled stream from section IV during the switching interval, in order to reduce the fluctuation of salt or solvent strength in the columns. Moreover, we also present a comparison of two strategies of modeling, the gradient SMB model and the equivalent gradient TMB model, for the prediction of internal concentration profiles in gradient SMB chromatography with open loop and closed loop, respectively. (C) 2007 American Institute of Chemical Engineers.