Despite the small number of leukocytes relative to erythrocytes in the circulation, leukocytes contribute significantly to organ blood flow resistance. The present study was designed to investigate whether interactions between leukocytes and erythrocytes affect the pressure-flow relationship in a hemodynamically isolated rat gracilis muscle. At constant arterial flow rate, arterial pressure was increased significantly when relatively few physiological counts of leukocytes were added to a suspension containing erythrocytes at physiological hematocrits. However, the arterial pressure after perfusion of similar numbers of isolated leukocytes without erythrocytes was only slightly increased. An increase in resistance was also observed when leukocytes were replaced with 6-µm microspheres. We propose a new mechanism for increasing the hemodynamic resistance that involves hydrodynamic interactions between leukocytes and erythrocytes. In the presence of larger and less deformable leukocytes, erythrocytes move through capillaries more slowly than without leukocytes. Therefore erythrocytes are displaced from their axial positions. Slowing and radial displacement of erythrocytes serve to increase the relative apparent viscosity attributable to erythrocytes, thereby causing a significant elevation of organ blood flow resistance.