Our objective was to investigate experimentally the easily overlooked effect of the clinical use of colloidal plasma substitutes on tissue perfusion. The experimental animals were dogs, and the study was carried out using several independent rheological experimental methods. The following are the principal findings: 1) Based on the observations made under a microscope, the stability of blood suspensions was best maintained by dextran-40 (Dex 40) and hydroxyethyl starch (HES0.55; Hespander), both of which cause little rouleaux formation by erythrocytes. In addition, the electronegativity of the erythrocyte membrane was simultaneously elevated. 2) The blood viscosity was greatly affected by the hematocrit and the serum protein concentration. 3) At a high shear rate, the blood viscosity among these colloidal plasma substitutes showed no great difference after infusion; in contrast, at a low shear rate, the blood viscosity after infusion of Dex 40 or HES0.55 was lower than after other substitutes. 4) The ratio of the viscosity at a low shear rate to the viscosity at a high shear rate is more significant and useful as a clinical indicator. On the basis of the preceding findings, Dex 40 and HES0.55 were generally superior to the other substitutes, especially HES0.55.