Systems and methods for performing a therapeutic red blood cell exchange procedure are disclosed. In one aspect, a system includes a first flow path for flowing whole blood from a patient. A separator communicates with the first flow path for separating at least red blood cells from plasma. Second and third flow paths communicate with the separator for respectively flowing the separated plasma and red blood cells from the separator. A flow controller is associated with the flow paths to control fluid communication between the flow paths. The controller is configured to perform the procedure to achieve a target fraction of patient cells remaining, target hematocrit, and a target patient fluid volume change at the completion of the procedure based on data input by the operator.