The effects of leukocyte (WBC) sequestration in the capillary network on resistance to flow (RA-V) were obtained during bolus infusions of WBCs in cremaster muscle (hamster). RA-V was calculated from simultaneous measurements of arteriole to venule pressure drop and arteriolar red cell velocity. Bolus infusions of red cells (RBCs) alone resulted in a 5% decrease in RA-V, due to the clearance of circulating WBCs from the network. Infusions of RBCs with leukocrits of one to nine times systemic resulted in insignificant transient increases in RA-V of 5 to 10%. The effect of WBC activation was studied by their incubation in N-formyl-methionyl-leucyl-phenylalanine (FMLP) to activate (and stiffen) the polymorphonulear WBCs (PMNs) or phorbal myristate acetate (PMA) to activate all WBCs in the bolus. Compared with normal WBCs, infusions of mixtures of RBCs and activated WBCs had no significant effect on the transient increase in resistance as the bolus traversed the capillary network. However, mixtures with either normal or FMLP-treated WBCs increased the steady state RA-V in proportion to the cumulative number of WBCs infused, due to residual capillary plugging following washout of the bolus. The cumulative infusion of 20 × 106 normal or FMLP-activated WBCs resulted i a 25% increase in RA-V above baseline. With PMA activation, cumulative infusions of only 5 × 106 WBCs in the RBC suspension also resulted in a 25% increase in RA-V, which was three times the increase obtained for an equal number of FMLP-activated WBCs. Following the cumulative infusion of 12 × 106 PMA-activated WBCs, RA-V increased inordinately to approximately 250% of baseline. These substantially greater increases in capillary plugging and RA-V with PMA activation were in accord with the threefold greater number of stiffened lymphocytes (which do not respond to FMLP) relative to PMNs in the boli. Thus, capillary plugging by activated WBCs may have a far greater detrimental effect on blood flow through the microvasculature compared to normal WBCs, and the extent of this effect is strongly dependent on the number of activated WBCs in the circulation.