Upon inflammation, stimulated, but not resting T lymphocytes cross the blood‐brain barrier and migrate into the central nervous system. This study shows that direct contact between stimulated T lymphocytes and human brain microvascular endothelial cells (HB‐MVEC) induces phenotypic and functional changes on the latter cells. Plasma membranes isolated from stimulated T lymphocytes (S‐PM) up‐regulated the expression of intercellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1), and E‐selectin on isolated HB‐MVEC. In addition, HB‐MVEC activated by S‐PM secreted interleukin (IL)‐6 and IL‐8. The levels of ICAM‐1, E‐selectin, IL‐6, and IL‐8 expressed in S‐PM‐activated HB‐MVEC were similar to those observed with 1000 U/ml tumor necrosis factor (TNF). In contrast, VCAM‐1 expression was 15% of that induced by TNF. Inhibitors of TNF diminished (≤ 45 %), but did not abolish the expression of cell adhesion molecules and IL‐6 induced by S‐PM, IL‐8 production being insignificantly affected (≤ 10 %). This suggests that membrane‐associated TNF was partially involved in HB‐MVEC activation. The present study demonstrates that stimulated T lymphocytes are able to activate HB‐MVEC upon direct cell contact. This novel mechanism of inducing the expression of cell adhesion molecules may prompt the initial adhesion of stimulated T lymphocytes to brain endothelium.