Hemophagocytic syndrome (HPS) is a clinicopathologic syndrome that can be precipitated by a variety of causes and is characterized by a systemic activation of macrophages, which are induced to undergo phagocytosis. Chemokines play an important role in the inflammatory cell recruitment into tissues. We examined the expression of chemokines and cytokines in tissues exhibiting histologic evidence of HPS in a variety of settings: peripheral T-cell lymphoma, three patients; nasal T/NK cell lymphoma, one patient; subcutaneous panniculitis-like T-cell lymphoma, one patient; and chronic EBV infection, one patient. Compared with control tissues, we found elevated macrophage inflammatory protein-1alpha (MIP-1alpha) and interferon-gamma (IFN-gamma) expression, but not macrophage-derived chemotactic factor (MDC) or TNF-alpha, in tissues of patients with HPS irrespective of the cause or setting. MIP-1alpha can promote macrophage chemotaxis and IFN-gamma promotes macrophage activation. Elevated expression of IP-10 and monokine induced by IFN-gamma (Mig) was also detected in tissues exhibiting features of HPS, providing an explanation for the occurrence of chemoattraction of T-cells and NK cells. Immunohistochemical analysis of tissues with evidence of phagocytic activity in that site showed MIP-1alpha characteristically localized to endothelial cells of blood vessels and splenic sinuses, lymphocytes, and macrophages. These results provide evidence for MIP-1alpha chemokine expression in tissues from patients with HPS and suggest that MIP-1alpha may play an important role in the pathogenesis of the hemophagocytic syndrome.