The distribution and lineage of vascular cell adhesion molecule-1 (VCAM-1)-positive cells was investigated in 43 lesions from the brain tissue of patients with multiple sclerosis (MS). Numerous VCAM-1-positive macrophages/microglia were detected at the edges of MS lesions. Quantitative analysis of 6 active, 7 chronic active, and 4 chronic inactive MS lesions identified most VCAM-1-positive cells at the actively demyelinating borders of active (102/mm3) and chronic active (29/mm3) lesions, but rarely in chronic inactive lesions (4/mm3). Further, approximately 17% of the VCAM-1-positive cells closely apposed or surrounded oligodendrocyte perikarya at the edges of active and chronic active lesions that were sites of ongoing demyelination. Endothelial cells were VCAM-1-negative in both lesion and non-lesion MS brain tissue. This report is the first to document direct microglial interaction with oligodendrocytes in MS.