Leukocyte migration into inflammatory lesions is controlled by adhesion molecules. L-selectin is the adhesion molecule on leukocytes that is responsible for making the initial contact with endothelium. After establishing this contact, L-selectin is shed from the cell surface and present in the circulation as a functional soluble receptor. To investigate this initial adhesive event, we evaluated the presence of soluble L-selectin (sL-selectin) in serum and CSF of patients with multiple sclerosis (MS), viral encephalitis, and controls. MS patients with active, gadolinium-enhancing lesions on magnetic resonance imaging had significantly higher sL-selectin serum levels than controls (P < 0.05). These levels in MS patients correlated with the size of the enhancing lesions (P < 0.05), and with sL-selectin levels in CSF (P < 0.001). In viral encephalitis, in contrast, sL-selectin is elevated in CSF only (P < 0.001) and may derive from intrathecal leukocytes. These results show that the earliest adhesive events mediated by L-selectin indeed operate in active MS, and that sL-selectin will be of value in quantitating the extent of this inflammatory process.