The neutrophil Mac-1 and gp100^MEL-14 adhesion proteins are involved in neutrophil extravasation during inflammation. Both the expression and activity of Mac-1 are greatly increased after neutrophil activation. In contrast, neutrophils shed gp100^MEL-14 from the cell surface within 4 minutes after activation with chemotactic factors or phorbol esters, releasing a 96-kilodalton fragment of the antigen into the supernatant. Immunohistology showed that gp100^MEL-14 was downregulated on neutrophils that had extravasated into inflamed tissue. The gp100^MEL-14 adhesion protein may participate in the binding of unactivated neutrophils to the endothelium; rapid shedding of gp100^MEL-14 may prevent extravasation into and damage of normal tissues by activated neutrophils.