Three simulated moving bed (SMB) cascade systems with two trains are studied to separate only one of the intermediate retained components from a quaternary mixture. The three systems are a cascade with two four-zone SMBs (4 + 4), a cascade with a two-zone SMB/chromatography and a four-zone SMB (2 + 4), and a cascade with a single-column analogue and a four-zone SMB (1 + 4). To reduce desorbent use, an unwanted product containing desorbent is recycled from the second train to the first train. The minimum D-total/F is calculated with the local equilibrium model. Optimum operating conditions are determined with a binary coded genetic algorithm for separation of a model system of nucleosides. In the optimization, purity and recovery were simulated by Aspen Chromatography. Compared to the system 4 + 4, the separation constraints of systems 1 + 4 and 2 + 4 were more restrictive, but they used less desorbent at the same product purity and same productivity. For example, for a product purity of 95.0%, desorbent to feed ratios for systems 2 + 4 and 1 + 4 were 6.07 and 8.33, respectively, while that of system 4 + 4 was 14.26. In addition, systems 1 + 4 and 2 + 4 require fewer columns than system 4 + 4.