Adhesion molecules are important in T-cell trafficking to sites of inflammation. We determined levels of circulating vascular cell adhesion molecule-1 (VCAM-1), L-selectin, and E-selectin in the serum of 147 patients with definite multiple sclerosis of the remitting-relapsing or secondary progressive type. Soluble VCAM-1 and L-selectin concentrations were increased compared to levels in a large group of control subjects. Levels were highest in patients with gadolinium-enhancing lesions on magnetic resonance imaging (VCAM-1: 1,011 ± 276 vs 626 ± 87 ng/ml; L-selectin: 1,130 ± 272 vs 793 ± 207 ng/ml [mean ± standard deviation]; p > 0.0001 vs patients without enchancing lesions). Serum levels of soluble tumor necrosis factor receptor (60 kd) were also raised (2.64 ± 1.23 vs 2.17 ± 0.69 ng/ml in subjects with other neurological diseases and 2.1 ± 0.77 ng/ml in healthy control subject; p < 0.05). Soluble VCAM-1 and L-selectin levels were correlated to concentrations of soluble tumor necrosis factor receptor. In 13 patients with viral encephalitis, similar observations were made. Raised levels of soluble VCAM-1 and L-selectin probably reflect cytokine-induced endothelial cell and T-lymphocyte/monocyte activation occurring in the process of T-cell migration into the central nervous system. Tumor necrosis factor-alpha may be critically involved.