The leukocyte integrins have critical roles in host defense and inflammatory tissue injury. We found that integrin α D β 2, a novel but largely uncharacterized member of this family, is restricted to subsets of macrophages and a small population of circulating leukocytes in wild-type mice in the absence of inflammatory challenge and is expressed in regulated fashion during cytokine-induced macrophage differentiation in vitro. α D β 2 is highly displayed on splenic red pulp macrophages and mediates their adhesion to local targets, identifying key functional activity. In response to challenge with Plasmodium berghei, a malarial pathogen that models systemic infection and inflammatory injury, new populations of α D+ macrophages evolved in the spleen and liver. Unexpectedly, targeted deletion of α D conferred a survival advantage in P. berghei infection over a 30-day observation period. Mechanistic studies demonstrated that the increased survival of α D−/− animals at these time points is not attributed to differences in magnitude of anemia or parasitemia or to alterations in splenic microanatomy, each of which is a key variable in the natural history of P. berghei infection, and indicated that an altered pattern of inflammatory cytokines may contribute to the difference in mortality. In contrast to the outcome in malarial challenge, death of α D−/− animals was accelerated in a model of Salmonella sepsis, demonstrating differential rather than stereotyped roles for α D β 2 in systemic infection. These studies identify previously unrecognized and unique activities of α D β 2, and macrophages that express it, in host defense and injury.