Systemic and microvascular hemodynamic responses to extreme hemodilution with low and high viscosity plasma expanders were studied using the hamster window chamber model to determine whether plasma viscosity is a factor in homeostasis during extreme anemic conditions. Moderated hemodilution was induced by two isovolemic steps performed with 6% dextran 70 kDa until systemic hematocrit (Hct) was reduced to 18% (Level 2). A third isovolemic step hemodilution reduced Hct to 11% using either a low viscosity plasma expander (6% dextran 70 kDa, 2.8 cP, LVPE) or a high viscosity plasma expander (6% dextran 500 kDa, 5.9 cP, HVPE). Measurement of systemic parameters, cardiac output (CO), organ flow distribution, microhemodynamics and functional capillary density (FCD) were performed after each exchange dilution. Fluorescent labeled microspheres were used to measure organ blood flow (brain, heart, kidney, liver, lung, spleen, and window chamber). Final blood and plasma viscosities after the entire protocol were 2.1 and 1.4 cP for LVPE and 2.8 and 2.2 cP for HVPE (baseline: 4.2 and 1.2 cP). HVPE had a significantly greater mean arterial pressure (MAP) and CO than LVPE, without increasing vascular resistance. FCD was significantly higher for HVPE (87 ± 7 % of baseline) vs. LVPE (42 ± 11 % of baseline). Increased MAP, CO and shear stress mediated factors could be the possible mechanisms that maintained organ and microvascular perfusion after exchange with HVPE compared to LVPE. Microhemodynamic was found to correspond to microspheres measured perfusion in vital organs (heart, liver and lung).