A blood processing system (2, 100) configured for performing a red blood cell exchange procedure, comprising: a blood separation device configured to separate whole blood from a blood source into a first component including separated red blood cells and a second component including separated plasma; an inlet pump (30, 128) operable to convey whole blood from the blood source into the blood separation device at a prescribed blood draw rate Q 3; a plasma pump (28, 132) operable to convey separated plasma from the blood separation device to the blood source at a plasma flow rate Q 5; a replacement fluid pump (26, 130) operable to convey a volume V R of replacement fluid to the source at a replacement fluid flow rate Q 1; and a controller (36, 138) programmed to provide the blood draw rate Q 3 and the volume V R of replacement fluid based on input from a sensor or a measurement, from an operator or as default values; calculate the plasma flow rate Q 5 and the replacement fluid flow rate Q 1 based at least in part on the blood draw rate Q 3 and the volume V R of replacement fluid to be flowed to the source, adjust the operation of the replacement fluid pump (26, 130) to achieve the calculated replacement fluid flow rate Q 1, and adjust the operation of the plasma pump (28, 132) to achieve the calculated plasma flow rate Q 5, wherein the plasma flow rate Q 5 and the replacement fluid flow rate Q 1 are calculated so as to simultaneously deplete the volume V R of replacement fluid and achieve one other prescribed process parameter, wherein the prescribed process parameter is one of maintaining a hematocrit of the blood of the source and a fluid volume of the source at constant levels, maintaining the hematocrit of the blood of the source at a constant level while changing the fluid volume of the source from an initial level to a prescribed level, and changing the hematocrit of the blood of the source from an initial level H T0 to a prescribed level H TF, and either maintaining the fluid volume of the source at a constant level or changing the fluid volume of the source from an initial level to a prescribed level by a difference Δ V. a blood separation device configured to separate whole blood from a blood source into a first component including separated red blood cells and a second component including separated plasma; an inlet pump (30, 128) operable to convey whole blood from the blood source into the blood separation device at a prescribed blood draw rate Q 3; a plasma pump (28, 132) operable to convey separated plasma from the blood separation device to the blood source at a plasma flow rate Q 5; a replacement fluid pump (26, 130) operable to convey a volume V R of replacement fluid to the source at a replacement fluid flow rate Q 1; and a controller (36, 138) programmed to provide the blood draw rate Q 3 and the volume V R of replacement fluid based on input from a sensor or a measurement, from an operator or as default values; calculate the plasma flow rate Q 5 and the replacement fluid flow rate Q 1 based at least in part on the blood draw rate Q 3 and the volume V R of replacement fluid to be flowed to the source, adjust the operation of the replacement fluid pump (26, 130) to achieve the calculated replacement fluid flow rate Q 1, and adjust the operation of the plasma pump (28, 132) to achieve the calculated plasma flow rate Q 5, wherein the plasma flow rate Q 5 and the replacement fluid flow rate Q 1 are calculated so as to simultaneously deplete the volume V R of replacement fluid and achieve one other prescribed process parameter, wherein the prescribed process parameter is one of maintaining a hematocrit of the blood of the source and a fluid volume of the source at constant levels, maintaining the hematocrit of the blood of the source at a constant level while changing the fluid volume of the source from an initial level to a prescribed level, and changing the hematocrit of the blood of the source from an initial level H T0 to a prescribed level H TF, and either maintaining the fluid volume of the source at a constant level or changing the fluid volume of the source from an initial level to a prescribed level by a difference Δ V.