Phagocytosis of apoptotic neutrophil granulocytes by macrophages at inflammatory sites is an important determinant of the process by which inflammation resolves. We demonstrate that phagocytosis of apoptotic neutrophils, but not apoptotic lymphocytes, by human monocyte-derived macrophages is augmented rapidly following ligation of CD44 by bivalent Abs in vitro. Previously defined inhibitors of apoptotic cell recognition did not affect CD44-augmented phagocytosis of apoptotic neutrophils, suggesting that unique molecular recognition pathways are involved. These observations, together with the lack of effect of CD44 Abs upon macrophage phagocytosis of zymosan or Ig-opsonized erythrocytes, imply that CD44 may regulate the differential clearance of apoptotic leukocytes during evolution of inflammatory responses. This represents a novel role for CD44 in inflammation and tissue repair.