MRL/fas(lpr) mice are affected by a systemic autoimmune disease that results in widespread leukocytic infiltration of the vasculature, including in the skin. The molecular pathways responsible for this leukocyte recruitment are poorly understood. Therefore, the aim of these experiments was to examine the mechanisms of leukocyte trafficking in the dermal microvasculature of MRL/fas(lpr) mice. Intravital microscopy was used to examine leukocyte rolling and adhesion in dermal postcapillary venules of MRL/fas(lpr) mice at 8, 12, and 16 wk of age. When compared with age-matched BALB/c and MRL(+/+) (nondiseased) mice, leukocyte rolling and adhesion in MRL/fas(lpr) mice were significantly enhanced at 12 wk of age, and remained elevated at 16 wk of age. At 8 and 12 wk, leukocyte rolling in all three strains was almost entirely inhibited by an anti-P-selectin mAb. In contrast, at 16 wk some (approximately 10%) leukocyte rolling persisted following P-selectin blockade. This residual rolling was predominantly inhibitable with an anti-E-selectin mAb; however, treatment with anti-E-selectin mAb alone had a minimal effect. P-selectin-deficient MRL/fas(lpr) mice also displayed leukocyte rolling that was significantly lower than in wild-type MRL/fas(lpr) mice. However, in these mice, leukocyte adhesion remained at the elevated levels observed in wild-type MRL/fas(lpr) mice. This adhesion was eliminated by chronic treatment with anti-E-selectin mAb. These findings indicate that leukocyte-endothelial cell interactions are enhanced in the dermal microvasculature of MRL/fas(lpr) mice above the age of 12 wk. Furthermore, the data suggest that the endothelial selectins share overlapping roles in mediating this enhanced leukocyte recruitment.