The mechanisms underlying leukocyte recruitment in systemic lupus erythematosus (SLE) are unclear. Leukocytes from SLE patients display increased integrin expression, but whether this results in an increased capacity to undergo adhesive interactions has not been investigated. Therefore, the aim of this study was to identify alterations in the capacity of leukocytes from SLE patients to undergo interactions with various substrates under flow conditions. Blood from SLE patients was examined in a flow chamber assay, and rolling, adhesion and post-adhesion spreading assessed on platelet monolayers or VCAM-1. P-selectin-dependent neutrophil rolling on platelet monolayers did not differ between SLE patients and healthy controls. Similarly, lymphocyte adhesion on VCAM-1 did not differ between patients and controls. However, post-adhesion spreading on VCAM-1 was significantly increased in lymphocytes from SLE patients. These parameters were unaffected by overall disease activity, presence of organ damage or prednisolone usage. However, leukocyte spreading on VCAM-1 was elevated in patients with evidence of active renal disease. These findings indicate that lymphocytes from SLE patients have an increased propensity to undergo post-adhesion spreading, a key preliminary step in leukocyte transmigration. This behavior may contribute to lymphocyte infiltration in SLE patients and may represent a novel biomarker of lupus nephritis.