The chemokine receptors CXCR1 and CXCR2 critically determine the functional properties of granulocytes. To obtain insight in the regulation of these receptors during infection, CXCR expression was determined on blood granulocytes by fluorescence-activated cell sorter analysis in healthy subjects intravenously injected with lipopolysaccharide (LPS) and in patients with active tuberculosis. In healthy subjects, LPS induced a transient decrease in granulocyte CXCR1 and CXCR2 expression, whereas in tuberculosis patients, only CXCR2 showed reduced levels. In whole blood in vitro, LPS, lipoarabinomannan from Mycobacterium tuberculosis, and lipoteichoic acid from Staphylococcus aureus reduced expression of CXCR2 but not of CXCR1. CXCR2 down-regulation induced by LPS or tumor necrosis factor-alpha in vitro was abrogated by a p38 mitogen-activated protein kinase (MAPK) inhibitor. Granulocytes may down-regulate CXCR2 and, to a lesser extent, CXCR1 at their surface upon their first interaction with mycobacterial or bacterial pathogens by a mechanism that involves activation of p38 MAPK.