This study analyzes for the first time the residence time distribution in a size-exclusion simulated moving bed (SMB) process. In an SMB, the raffinate port is located downstream from the feed port, whereas the extract port is located upstream from the feed port. The location of the product ports and periodic port movement results in a residence time distribution that strongly depends on solute injection time. The earlier a fast-moving solute is injected during the switching period, the earlier it exits the raffinate port. In contrast, the earlier a slow-moving solute is injected during the switching period, the later it exits the extract port. Furthermore, only a fraction of the stream is drawn as the raffinate product or the extract product. The rest is recycled. The recycle results in the splitting of a differential pulse into a pulse train with diminishing magnitude. The shape of the pulse train depends on the pulse injection time. A large recycle ratio, which results from a low selectivity, causes a long decay of the pulse train and increases tailing of the residence time distribution curve. Mass-transfer effects broaden the pulse train and the residence time distribution. To shorten the residence time of a fast-moving solute, one can increase the flow rate of zone II, decrease the length of zone III, or feed during the first half of the switching period. To shorten the residence time of a slow-moving solute, one can decrease the flow rate of zone III, decrease the length of zone II, or feed during the second half of the switching period. Rate model simulations show that these strategies can significantly reduce the residence time of insulin in SMB.