Recent studies suggest that Leishmania major promastigotes infect cultured macrophages in a stealthy fashion, activating little or no host gene expression and often interfering with the host's ability to respond to further stimulation. Here we examined macrophage transcription at early times following infection, when virulent parasites must execute steps required for survival. Stationary-phase promastigotes induced rapid and transient expression of transcripts of the chemokines JE (human MCAF/MCP-1) and KC (human GRO) in bone marrow-derived macrophages from BALB/c mice. JE and KC expression rose four- to sixfold shortly after infection and returned to uninduced levels by 4-24 hr. In contrast, chemokines MIP-1alpha, C10, and RANTES were not induced, nor were TGF-beta, IL-10, IL-12, or i-NOS. Chemokine induction did not occur following ingestion of latex beads, implicating a parasite-specific stimulus. Elevated expression of a subset of chemokines is the earliest known transcriptional response of macrophages to L. major infection and potentially may provide a signal for the initiation of downstream immunological responses which occur in vivo, such as cytokine induction and chemotaxis of monocytes and macrophages. Thus, Leishmania has a remarkable ability to take an active role in either inducing or preventing the expression of distinct sets of host genes during macrophage invasion and successful intracellular parasitism.