We evaluated the effect of antibodies directed against a leukocyte adhesion molecule (ICAM-1) in an embolic model of stroke followed by thrombolysis with tissue plasminogen activator (tPA). To test whether reperfusion injury after ischemia was related to white cell adhesion, microclots were injected into carotid circulation. The conditions examined were control, alpha-ICAM 5 min following ischemia, tPA 30 min after ischemia, and the combination of alpha-ICAM and tPA. alpha-ICAM and tPA both increased the amount of clot necessary to produce permanent neurological damage. Combined therapy was no more effective than either substance alone. A similar outcome was obtained when tPA was delayed until 90 min postischemia. When thrombolysis was delayed 3 h following embolism, neither tPA nor the tPA/alpha-ICAM combination reduced neurological damage. Thus, the alpha-ICAM antibody and tPA each effectively reduced neurological damage but the interaction was not significant.