A five-zone simulated moving bed (SMB) process for ternary separation has been developed previously and applied to the purification of biochemicals in the literature. Although this process was effective to some degree in many of previous research studies, its separation performance was always limited by the presence of overlap between the highest-affinity and the intermediate-affinity solutes. Since a proper control of the overlap was almost impossible under the current configuration and operation method, the application scope of a conventional five-zone SMB was restricted within the separation tasks that permitted either relatively medium purities or low throughput. To overcome such a limitation, an efficient operation strategy for improving the five-zone SMB performance was proposed in this study. The core of the proposed strategy is to partially collect the product stream by alternate opening and closing of the extract-2 port, which is in charge of recovering the intermediate-affinity solute molecules. Simultaneously, the zone II flow rate during the port-opening state is adjusted properly for complete desorption of the intermediate-affinity solute in zone II. The application of such a strategy was found to improve the five-zone SMB performance dramatically. One of the noteworthy improvements was that all three products could be recovered with extremely high purities at the same time. Furthermore, a marked increase in the throughput could also be obtained under the given purity requirements. Therefore, the strategy proposed in this study is expected to substantially upgrade the five-zone SMB performance, allowing its application to the separation tasks that demand either high purities or high throughput.