The CXC chemokine receptor CXCR4 and its unique ligand SDF-1 (stromal-derived factor-1) play critical roles for the retention of hematopoietic cells within the bone marrow (BM) and for their mobilization into the circulation. Lithium often produces neutrophilia in psychiatric patients, but the mechanism of mobilization related to neutrophilia has not been fully clarified. We showed here that lithium dose-dependently reduces the levels of surface CXCR4 protein and mRNA in neutrophils, but not in lymphocytes. The chemotactic migration of neutrophils in response to SDF-1 was reduced after a pre-incubation with lithium. We provide evidence that lithium down-regulates the CXCR4 expression of neutrophils and it attenuates their responsiveness to SDF-1. Our studies support the concept that down-regulation of CXCR4 is one of the mechanisms by which causes neutrophilia.