The purpose of this study was to examine the relationship between increased capillary network resistance due to leukocyte capillary plugging and tissue injury following ischemia-reperfusion (I/R). After a 30-min complete ischemia in rat spinotrapezius muscle, the frequency and duration of leukocyte capillary plugging were measured throughout capillary networks and used to estimate the increase in network flow resistance for I/R alone, I/R with phalloidin (Pl), and I/R with both Pl and cytochalasin D. Propidium iodide (PI) was used to label nonviable muscle cell nuclei within the volume of tissue supplied by the capillary network, and counts were made before ischemia, immediately after reperfusion, and 1 h postreperfusion. For I/R alone and I/R + Pl there is a linear correlation between the increase in resistance (up to 29%) and the increase in the number of PI-positive nuclei during the reperfusion period. With both Pl and cytochalasin D present in the superfusate, the resistance increase was abolished and the amount of tissue damage during reperfusion was minimized. The results indicate that the increase in resistance is linearly related to the tissue damage and that a reduction of the leukocyte stiffness reduces the injury.