IL-8 is an inflammatory CXC chemokine involved in neutrophil recruitment and activation in various inflammatory conditions. The transcriptional profile induced by IL-8 in human neutrophils was analyzed using high-density oligonucleotide arrays and compared with that of the prototypic phagocyte activator LPS. As expected, LPS induced a major effect on the cell transcriptome, upregulating 116 (0.93%) and downregulating 70 (0.56%) of the transcripts. IL-8 induced a less profound modulation of the cell transcriptome, with upregulation of 30 (0.25%) and downregulation of 6 (0.04%) of the transcripts. Although the two proinflammatory mediators induced partially overlapping transcriptional profiles (50.0% of IL-8-responsive genes were concordantly regulated by LPS), IL-8 also modulated a significant number of genes unresponsive to LPS, including soluble mediators, membrane receptors, signaling molecules, and regulators of transcription and translation. A set of IL-8-inducible genes was related to cell motility, possibly a strategy to prepare for migration into tissues. Analysis of the IL-8-responsive gene IL-1beta at the protein level revealed that transcript induction was not followed by protein production. Neutrophils stimulated with IL-8, however, showed a significant increase in IL-1beta secretion after subsequent exposure to LPS. Thus, the effect of IL-8 at the transcriptional level could provide a synergistic effect with microbial products for neutrophil activation.