The urokinase receptor (uPAR) plays an important role in regulation of fibronolysis, cell migration, and adhesion. In this study, we examined whether uPAR plays a role in modulating efferocytosis of neutrophils. Macrophages from uPAR-/- mice demonstrated enhanced ability to engulf viable wild-type (WT) neutrophils in vitro and in vivo in the lungs. The increased phagocytic activity of uPAR-/- macrophages was abrogated by incubation with soluble uPAR (suPAR), arginine-glycineaspartic acid (RGD)-containing peptides, or anti-integrin antibodies. There was increased uptake of viable uPAR -/- neutrophils by WT macrophages. Incubation of uPAR-/- neutrophils with suPAR or antiintegrin antibodies diminished uptake by WT macrophages to baseline. Uptake of uPAR-/- neutrophils by uPAR -/- macrophages was not enhanced. However, incubation of uPAR -/- neutrophils or uPAR-/- macrophages, but not both, with suPAR enhanced the uptake of viable uPAR-/- neutrophils by uPAR-/-macrophages. The adhesion of WT neutrophils to uPAR-/- macrophages was higher than to WT macrophages. uPAR-/- neutrophils demonstrated increased adhesion to suPAR, which was abrogated by blocking of low-density lipoprotein related protein and integrins. Expression of uPAR on the surface of apoptotic neutrophils was reduced compared with levels on viable neutrophils. These results demonstrate a novel role for uPAR in modulating recognition and clearance of neutrophils. © 2009 by The American Society of Hematology.